FOR OCULAR RADIOTHERAPY

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application No. 63/381, 454, filed on October 28, 2022. The entire contents of this application are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0002] This invention relates to the field of radiotherapy and more specifically to the subfield of brachytherapy, and to radionuclide brachytherapy sources (RBS) used to treat conditions of the eye, such as but not limited to diabetic retinopathy (DR) , diabetic macular edema (DME) , cystoid macular edema (CME) , macular edema (ME) secondary to central retinal vein occlusion (CRVO) , and ME secondary to branch retinal vein occlusion (BRVO) .

2. Description of the Related Art

[0003] Central Serous Chorioretinopathy (CSCR) is a condition affecting the eye, which may result in visual impairment and typically presents unilaterally in one eye, but bilateral involvement may be present in up to 40% of cases. CSCR typically causes blurred or distorted vision, e.g. , metamorphopsia . Patients may also report micropsia (objects appearing smaller than they really are) and/or color vision disturbances. Temporary hyperopia (farsightedness) is generally present. CSCR may also cause a blurred or gray spot in the central visual field, which commonly occurs when the retina is detached. Reduced visual acuity may resolve upon resolution of CSCR, or may persist after the fluid accumulation that is associated with CSCR has dispersed and CSCR has resolved.

[0004] CSCR is generally regarded as being of unknown cause, and mostly affects white males aged 20-50 years of age. It is believed that CSCR is associated with exogenous corticosteroid use. Further, CSCR is also believed to be associated with psychological stress, which in turn is associated with increased endogenous cortisol levels. Furthermore, other conditions associated with increased endogenous cortisol production, for example, Cushing syndrome and pregnancy, are also associated with an increased risk of developing CSCR. Cortisol is an endogenous glucocorticoid corticosteroid produced by the adrenal cortex, more specifically the zona fasciculata. Thus, it is believed that there is a general association between increased corticosteroid levels, whether from exogenous or endogenous sources, and the development of CSCR.

[0005] CSCR is characterized by an accumulation of fluid under the retina. In particular, fluid has the propensity to accumulate under the macula, an oval area surrounding the fovea, a small depression in the retina where retinal cones are particularly concentrated and where visual acuity is highest. The source of this fluid is typically hyperpermeable large vessels of the choroid, e.g. , large choroidal vessels. Serous fluid, leaked from the choroid, accumulates under the retina, causing small and localized detachments of the neurosensory layer of the macula (a part of the retina) , with or without concomitant detachment of the retinal pigment epithelium (RPE) , e.g., with or without pigment epithelial detachment (PED) . Detachment of the neurosensory layer results in the acute or chronic symptoms of met amorphopsia and other visual changes associated with CSCR.

[0006] The choroid is the vascular layer of the eye, sitting between the retina (deep to the choroid) and the sclera (superficial to the choroid) . The choroid provides blood flow to much of the retina. The choroid is divided into four layers. From most superficial (farthest from the retina) to deepest (closest to the retina) , the layers are: Haller' s layer, Sattler' s layer, choriocapillaris, and Bruch' s membrane. Haller's layer is the outermost (most superficial) layer of the choroid, and contains the largest choroidal vessels. Sattler' s layer is deep to Haller' s layer, and contains medium-sized choroidal vessels. The choriocapillaris is deep to Sattler' s layer, and contains capillaries, e.g. , small vessels. Bruch' s membrane is the innermost (e.g. , deepest) layer of the choroid, contains small vessels, and contains the basement membrane of both the choriocapillaris (on its most outermost side) and the basement membrane of the retinal pigment epithelium (on its innermost side) . [0007] The primary disease process involved in CSCR is serous fluid leakage from large choroidal vessels, subsequent fluid accumulation under the macula, and resultant detachment of the neurosensory layer of the macula, with or without PED. However, the pathophysiology of CSCR is multifactorial. Choroidal inflammation leads to vessel stasis, hyperpermeability, and thickening of the choroid. Thus, characteristic intermediate elements of CSCR' s pathology are choroidal hyperpermeability and choroidal thickening. In turn, increased tissue pressure on the RPE results, which results in damage to the RPE and may cause PED. Damage to the RPE decreases its effectiveness as a barrier, and choroidal fluid can thus cross the RPE, resulting in detachment of the neurosensory layer.

[0008] Furthermore, it is hypothesized that CSCR may result in the loss of polarity of the RPE. In a healthy eye, the RPE pumps fluid from the subretinal space into the choroid, keeping the retina in a relatively "dry" state. However, if polarity loss occurs, the RPE may reverse its pumping direction, pumping fluid from the choroid into the subretinal space. This may lead to subretinal fluid accumulation. Furthermore, choriocapillaris attenuation and hypoperfusion may result in elevated hydrostatic pressure and a resultant decrease in reabsorption performed by capillaries of the choriocapillaris. Again, this may contribute to subretinal fluid accumulation.

[0009] It is believed that mineralocorticoid receptors may also play a role, though their potential role is currently not well- defined. Experimental results have shown that intravitreal aldosterone injection results in dilatation of choroidal veins and choroidal congestion, which leads to subretinal fluid accumulation .

[0010] CSCR resolves spontaneously in the majority of cases and normal vision is regained, however recurrent retinal detachment is common. Because the condition is generally self-resolving, most clinicians will observe the patient for three to six months while attempting to correct any predisposing factors (e.g., tapering and stopping exogenous steroids, reducing the patient' s stress, etc.) . If CSCR and associated symptoms persist for over three to six months, or if detachment reoccurs, CSCR may be classified as chronic CSCR. Chronic CSCR leads to permanent pathophysiological changes, e.g. , foveal atrophy and changes to the retinal pigment epithelium. Chronic cases, if untreated, lead to permanent vision loss. Therefore, treatment is indicated for chronic CSCR. The most widely-utilized prior art treatments with the greatest level of evidence are laser photocoagulation and photodynamic therapy (PDT) .

[0011] Laser photocoagulation uses a laser to emit light which is absorbed by the targeted tissue, raising the tissue' s temperature and causing subsequent denaturation of proteins. Leakage sites on the retinal pigment epithelium are visualized with angiography and indicated by sites of hyperfluorescence, and these sites are then targeted with the laser. The leakage point is thus sealed, which decreases the time until subretinal fluid is cleared. However, laser photocoagulation suffers from several shortcomings. Laser photocoagulation is not an option if retinal pigment epithelial detachments involve the fovea, as the laser may cause permanent vision loss if used on the fovea. Laser photocoagulation is not proven to reduce the chance of recurrence of CSCR. Laser photocoagulation results in destruction of surrounding healthy retinal tissue, and may thus lead to the development of scotomas (spots of total or partial blindness in an otherwise normal field of vision) . Laser photocoagulation may also lead to choroidal neovascularization and further vision loss, particularly if the Bruch' s membrane is damaged by the laser. The potential development of these adverse effects thus requires frequent ophthalmological follow up for patients who have undergone laser photocoagulation. Laser photocoagulation is now considered an outdated treatment methodology by many clinicians .

[0012] Photodynamic therapy (PDT) is another option to treat CSCR. PDT is especially preferred over laser photocoagulation in cases where there is a leak on or near the fovea, where there are multiple leaks, and where there is diffuse decompensation of the retinal pigment epithelium. Verteporfin, a photosensitizer, is injected intravenously. Verteporfin reaches the eye via the bloodstream and is activated by light with a wavelength of 689 nm, producing short-lived reactive oxygen species and causing local damage and blockage of blood vessels in areas targeted by the light source. PDT thus seals sources of choroidal leaks, and results in choroidal vascular remodeling and choroidal hypoperfusion, further reducing choroidal hyperpermeability. PDT is generally considered to be more effective and safer than laser photocoagulation. Low fluence or half-fluence PDT, or low-dose or half-dose PDT (using a lower or half dose of verteporfin) has been found to be equally effective as standard fluence or standard dose PDT, with a more favorable adverse effect profile. However, PDT is still associated with shortcomings, such as a need to minimize UV exposure following treatment and photosensitivity. Standard fluence PDT has also been associated with significant damage to the choriocapillaris , although reduced-fluence PDT has decreased the prevalence of this complication .

[0013] Other treatments for CSCR have been tested with mixed results. Use of eplerenone, a mineralocorticoid antagonist, has been explored because of the potential role of mineralocorticoids in the development of CSCR. Epelerenone was found not superior to placebo in chronic CSCR (Lotery, A. et al. (2020) Lancet 395 (10220) , 294-303) . Other attempts at using ant i-cort icosteroid treatments have included finasteride, a 5a-reductase inhibitor with anti-androgenic properties, mifepristone, an antiprogesterone abort if acient , and rifampin, an ant itubercular antibiotic that accelerates the metabolism of corticosteroids in the liver by acting as a potent inducer of CYP3A4, the main enzyme responsible for steroid catabolism. However, studies on these agents have generally been small, results have generally been inconclusive, and none of these agents are currently considered standard of care. The same is true of anti-adrenergic agents that have been tested, for example, the selective beta-blocker metoprolol. Anti-VEGF therapy, including intravitreal injections with anti-VEGF agents like bevacizumab, has shown a lack of benefit in CSCR. The rationale for the use of anti-VEGF agents in CSCR has been widely questioned, because there is no known overexpression of VEGF in CSCR and CSCR is generally not associated with angiogenesis or neovascularization. Thus, the pharmacological rationale for anti-VEGF use in CSCR is generally considered lacking. Conflicting evidence or a general lack of demonstrated efficacy has thus confined most treatment of CSCR to either laser photocoagulation (a more limited treatment, considered outdated by some clinicians) or PDT (which is generally preferred over laser photocoagulation) .

[0014] Diabetes mellitus (DM) is the leading cause of blindness in the United States for people between 20 and 74 years of age. Patients with DM are 25 times more likely to become legally blind than patients without DM. DM may lead to diabetic retinopathy (DR) . DR may lead to diabetic macular edema (DME) and neovascularization. [0015] There are two stages of DR: non-proliferat ive and proliferative. Non-proliferat ive DR typically presents late in the first decade or early in the second decade of DR and is characterized by retinal vascular microaneurysms, blot hemorrhages, and cotton-wool spots. More severe forms of nonproliferative DR may be characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. Non-proliferat ive DR' s pathophysiology is defined by loss of retinal pericytes, increased retinal vascular permeability, alterations to retinal blood flow, and abnormal retinal microvasculature, all of which may lead to retinal ischemia.

[0016] Proliferative DR features neovascularization in response to retinal hypoxemia. Newly formed vessels appear near the optic nerve and/or macula and rupture easily, in turns causing vitreous hemorrhage, fibrosis, and retinal detachment.

[0017] Non-proliferat ive DR does not always evolve into proliferative DR, however the greater the severity of nonproliferative DR, the greater the likelihood of it evolving into proliferative DR within five years.

[0018] Both proliferative and non-proliferat ive DR may be associated with the development of clinically significant diabetic macular edema (DME) . DME is associated with a 25% chance of moderate vision loss over three years. The duration of DM and the degree of glycemic control are the primary factors that determine risk of developing retinopathy, though other factors such as hypertension, nephropathy, dyslipidemia, and genetics also play a smaller role.

[0019] The most effective existing approach for handling DR has been prevention via glycemic and blood pressure control in individuals with Type 1 or Type 2 DM. Interestingly, improved glycemic control is associated with transiently worsened DR during the first six to 12 months of improved control, though this is temporary and in the long-term, improved glycemic control is associated with improvements in DR.

[0020] Pharmacological treatments for DR include fenofibrate, which slows the progression of DR, and anti-VEGF therapy delivered via ocular injection, which may help preserve vision. Interventional procedures for DR include laser photocoagulation, which may also help preserve vision.

[0021] Cystoid macular edema (CME) is a retinal thickening of the macula due to disruption of the normal function of the blood- retinal barrier, leading to leakage of perifoveal retinal capillaries and subsequent accumulation of fluid with the intracellular spaces of the retina. Loss of vision occurs via retinal thickening and fluid collection that distorts the photoreceptors. A balance between osmotic pressure, hydrostatic force, capillary permeability, and tissue compliance maintains the normal retinal environment. An imbalance between capillary filtration rate and fluid removal from the retinal extracellular space may result in fluid accumulation in the cystoid spaces in the inner layers of the retina, particularly the outer plexiform layer (OPL) .

[0022] Vit reomacular traction (VMT) can exert fractional force on retinal cells, in turn causing release of inflammatory mediators, e.g., basic fibroblastic growth factor (bFGF) , vascular endothelial growth factor (VEGF) , and platelet derived growth factor (PDGF) . These in turn cause breakdown of the blood-retinal barrier and separation of the retina and RPE, lysis of Muller cells, and fluid leakage and edema. Foveal edema and retinal thickening typically result.

[0023] Prior art treatments of CME vary depending on the etiology of CME. Many cases of CME are self-limiting and do not require treatment. If CME persists over 3-4 months, treatment may be indicated. Medical treatment has included NSAIDs (to decrease prostaglandin production, as E2-prostaglandins are implicated in causing disruption of tight junctions in retinal capillaries) , corticosteroids (including corticosteroid-based intravitreal implants) , carbonic anhydrase inhibitors (help move fluid out of the retinal intracellular spaces) , and anti-VEGF agents. Surgical treatments in the prior art have included pars plana vitrectomy (PPV) , which has uneven efficacy depending on etiology (particularly in CME with significant nontract ional components) , and has the downside of being invasive. Other less-frequent ly utilized surgical treatments include laser photocoagulation, cryopexy, and various glaucoma-related procedures.

[0024] Central Retinal Vein Occlusion (CRVO) may also cause ME. CRVO is a form of retinal vein occlusion. It is a vascular occlusion of the central retinal vein, which in turn results in largely the same pathophysiological features of CME (listed above) , namely macular edema, retinal ischemia, and neovascular complications including glaucoma, vitreous hemorrhage, and retinal traction .

[0025] Prior art treatments of ME secondary to CRVO have included anti-VEGF and corticosteroids (injections or implants) to manage neovascularization and macular edema, respectively. Anti- VEGF injections are first-line therapy, and corticosteroids are generally second-line therapy. Panretinal photocoagulation has been used to treat neovascularization of the iris associated with ME secondary to CRVO .

[0026] Branch Retinal Vein Occlusion (BRVO) may also cause ME. BRVO is a form of retinal vein occlusion. It is a vascular occlusion of any branch of the central retinal vein, which in turn results in the largely the same pathophysiological features of CME (listed above) , namely macular edema, retinal ischemia, and neovascular complications including glaucoma, vitreous hemorrhage, and retinal traction.

[0027] Prior art treatments of ME secondary to BRVO have included anti-VEGF and corticosteroids (injections or implants) to manage neovascularization and macular edema, respectively. Anti- VEGF injections are first-line therapy, and corticosteroids are generally second-line therapy. Grid laser photocoagulation may be used to manage macular edema secondary to BRVO.

SUMMARY OF THE INVENTION

[0028] Preferred embodiments of the present invention provide devices and compositions that allow for irradiating a choroid target in an eye, as specified in the independent claims. Preferred embodiments of the invention are given in the dependent claims. Preferred embodiments of the present invention can be freely combined with each other if they are not mutually exclusive.

[0029] The present invention may be used to treat chronic serous chorioretinopathy (CSCR) . For example, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein said RBS is present in a cannula of a delivery device, the method comprising inserting said cannula into a potential space under a Tenon' s capsule of the eye, whereby the RBS is positioned over a choroid target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the choroid target, wherein a radioactive therapeutic portion of the RBS is consumed during the method.

[0030] Without wishing to limit the present invention to any theory or mechanism, the therapeutic doses are generally selected such that intimal proliferation of large choroidal vessels is increased while damages to vessels of the choriocapillaris and other radiosensitive structures of the eye, such as the lens, are minimized .

[0031] In some preferred embodiments, the therapeutic dose is from 6 to 18 Gy. In some preferred embodiments the therapeutic dose is 6-8 Gy. In some preferred embodiments the therapeutic dose is 6-10 Gy. In some preferred embodiments the therapeutic dose is 6-12 Gy. In some preferred embodiments the therapeutic dose is 6- 16 Gy. In some preferred embodiments the therapeutic dose is 8-10

Gy. In some preferred embodiments the therapeutic dose is 8-12 Gy.

In some preferred embodiments the therapeutic dose is 8-16 Gy. In some preferred embodiments the therapeutic dose is 8-18 Gy. In some preferred embodiments the therapeutic dose is 10-12 Gy. In some preferred embodiments the therapeutic dose is 10-14 Gy. In some preferred embodiments the therapeutic dose is 10-18 Gy. In some preferred embodiments the therapeutic dose is 12-16 Gy. In some preferred embodiments the therapeutic dose is 12-18 Gy. In some preferred embodiments the therapeutic dose is 14-18 Gy.

[0032] The therapeutic dose is delivered to a particular depth or range of depths, e.g., as measured from the interface of the sclera and the delivery device. For example, in some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-12 Gy.

[0033] In some preferred embodiments, the therapeutic dose is calculated based on the thickness of the choroid target. In some preferred embodiments, the thickness of the choroid target is measured using imaging.

[0034] In some preferred embodiments, the retina is exposed to less than 8 Gy. In some preferred embodiments, a choriocapillaris is exposed to less than 10 Gy. In some preferred embodiments, an interface of large choroidal vessels and a choriocapillaris is exposed to less than 12 Gy. In some preferred embodiments, the retina is exposed to less radiation than the choroid target. In some preferred embodiments, a choriocapillaris is exposed to less radiation than the choroid target.

[0035] As will be described herein, in some preferred embodiments, the therapeutic dose is fractionated over multiple sessions. For example, the therapeutic dose may be fractionated over at least two sessions. [0036] The dose is delivered to the choroid target in a period of time, e.g. , a dwell time. In some preferred embodiments, the dwell time is from 5 seconds to 10 minutes. In some preferred embodiments, the dwell time is from 5 seconds to 15 second. In some preferred embodiments, the dwell time is from 5 seconds to 30 seconds. In some preferred embodiments, the dwell time is from 5 seconds to 45 seconds. In some preferred embodiments, the dwell time is from 5 seconds to 1 minute. In some preferred embodiments, the dwell time is from 5 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 15 seconds to 30 seconds. In some preferred embodiments, the dwell time is from 15 seconds to 1 minute. In some preferred embodiments, the dwell time is from 15 seconds to 90 seconds. In some preferred embodiments, the dwell time is from 15 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 30 seconds to 1 minute. In some preferred embodiments, the dwell time is from 1 minute to 90 seconds. In some preferred embodiments, the dwell time is from 1 minute to 2 minutes. In some preferred embodiments, the dwell time is from 90 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 2 to 4 minutes. In some preferred embodiments, the dwell time is from 4 to 6 minutes. In some preferred embodiments, the dwell time is from 6 to 8 minutes. In some preferred embodiments, the dwell time is from 8 to 10 minutes. In some preferred embodiments the dwell time is from 5 to 10 minutes. In some preferred embodiments, the dwell time is greater than 10 minutes.

[0037] In some preferred embodiments the RBS delivers radiation to an irradiated area, e.g., having a diameter. In some preferred embodiments, the diameter of the irradiated area is up to 6 millimeters. In some preferred embodiments, the diameter of the irradiated area is up to 8 millimeters. In some preferred embodiments, the diameter of the irradiated area is up to 10 millimeters. In some preferred embodiments, the diameter of the irradiated area is up to 12 millimeters. In some preferred embodiments, the diameter of the irradiated area is 3-5 millimeters. The present invention is not limited to the aforementioned diameters.

[0038] In some preferred embodiments, the RBS is a source of ionizing radiation. In some preferred embodiments, the RBS is a source of particle radiation. In some preferred embodiments, the RBS is a source of beta radiation. In some preferred embodiments, the RBS is a source of X-ray radiation. In some preferred embodiments, the RBS is a source of multiple types of radiation.

[0039] In some preferred embodiments, the RBS is contained within a cannula. In some preferred embodiments the cannula is part of a delivery device. In some preferred embodiments, the delivery device comprises: a cannula comprising a curved distal portion adapted for placement around a portion of a globe of an eye; a curved proximal portion, the curved distal portion and the curved proximal portions being connected with each other at an inflection point where the direction of the curvature changes sign; and a straight proximal portion. In some preferred embodiments, the distal portion has a radius of curvature between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and the proximal portion has a radius of curvature between about an inner cross-sectional radius of the cannula and about 1 meter; and an angle 0i between a line [ 3 tangent to the distal portion and to the curved proximal portion at the inflection point and the straight proximal portion is between greater than about 0 degrees to about 180 degrees. The present invention is not limited to the aforementioned delivery device or cannula.

[0040] The present invention features a method of reducing hyperpermeability of large choroidal vessels in an eye of a patient in need thereof with central serous chorioretinopathy. In some preferred embodiments, the method comprises inserting a cannula into a potential space under a Tenon' s capsule of the eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a choroid target, and wherein a therapeutic dose of radiation is delivered to the choroid target.

[0041] The present invention features a method of increasing collagen deposition associated with large choroidal vessels in an eye of a patient in need thereof with central serous chorioretinopathy. In some preferred embodiments, the method comprises inserting a cannula into a potential space under a Tenon' s capsule of the eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a choroid target, and wherein a therapeutic dose of radiation is delivered to the choroid target. [0042] The present invention features a method of treating central serous chorioretinopathy in a patient in need thereof. In some preferred embodiments, the method comprises inserting a cannula into a potential space under a Tenon' s capsule of an eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a choroid target, and wherein a therapeutic dose of radiation is delivered to the choroid target.

[0043] Referring to the aforementioned methods, in some preferred embodiments, the therapeutic dose is from 6 to 18 Gy. In some preferred embodiments the therapeutic dose is 6-8 Gy. In some preferred embodiments the therapeutic dose is 6-10 Gy. In some preferred embodiments the therapeutic dose is 6-12 Gy. In some preferred embodiments the therapeutic dose is 6-16 Gy. In some preferred embodiments the therapeutic dose is 8-10 Gy. In some preferred embodiments the therapeutic dose is 8-12 Gy. In some preferred embodiments the therapeutic dose is 8-16 Gy. In some preferred embodiments the therapeutic dose is 8-18 Gy. In some preferred embodiments the therapeutic dose is 10-12 Gy. In some preferred embodiments the therapeutic dose is 10-14 Gy. In some preferred embodiments the therapeutic dose is 10-18 Gy. In some preferred embodiments the therapeutic dose is 12-16 Gy. In some preferred embodiments the therapeutic dose is 12-18 Gy. In some preferred embodiments the therapeutic dose : s 14-18 Gy.

[0044] In some pre: erred embodiments, th« retina is exposed to less than 8 Gy. In some preferred embodiments, a choriocapillaris is exposed to less than 10 Gy.

[0045] In some preferred embodiments, an interface of large choroidal vessels and a choriocapillaris is exposed to less than 12 Gy. In some preferred embodiments, a retina is exposed to less radiation than the choroid target. In some preferred embodiments, a choriocapillaris is exposed to less radiation than the choroid target .

[0046] As will be described herein, in some preferred embodiments, the therapeutic dose is fractionated over multiple sessions. For example, the therapeutic dose may be fractionated over at least two sessions.

[0047] The dose is delivered to the choroid target in a period of time, e.g. , a dwell time. In some preferred embodiments, the dwell time is from 5 seconds to 10 minutes. In some preferred embodiments, the dwell time is from 5 seconds to 15 second. In some preferred embodiments, the dwell time is from 5 seconds to 30 seconds. In some preferred embodiments, the dwell time is from 5 seconds to 45 seconds. In some preferred embodiments, the dwell time is from 5 seconds to 1 minute. In some preferred embodiments, the dwell time is from 5 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 15 seconds to 30 seconds. In some preferred embodiments, the dwell time is from 15 seconds to 1 minute. In some preferred embodiments, the dwell time is from 15 seconds to 90 seconds. In some preferred embodiments, the dwell time is from 15 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 30 seconds to 1 minute. In some preferred embodiments, the dwell time is from 1 minute to 90 seconds. In some preferred embodiments, the dwell time is from 1 minute to 2 minutes. In some preferred embodiments, the dwell time is from 90 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 2 to 4 minutes. In some preferred embodiments, the dwell time is from 4 to 6 minutes. In some preferred embodiments, the dwell time is from 6 to 8 minutes. In some preferred embodiments, the dwell time is from 8 to 10 minutes. In some preferred embodiments the dwell time is from 5 to 10 minutes. In some preferred embodiments, the dwell time is greater than 10 minutes.

[0048] In some preferred embodiments, the RBS delivers radiation to a treatment area, wherein a diameter of the treatment area is up to 8 millimeters. In some preferred embodiments, the RBS is a source of ionizing radiation. In some preferred embodiments, the RBS is a source of beta radiation. In some preferred embodiments, the RBS is a source of X-ray radiation. In some preferred embodiments, the RBS is a source of multiple types of radiation.

[0049] In some preferred embodiments, the RBS is contained within a cannula. In some preferred embodiments the cannula is part of a delivery device. In some preferred embodiments, the delivery device comprises: a cannula comprising a curved distal portion adapted for placement around a portion of a globe of an eye; a curved proximal portion, the curved distal portion and the curved proximal portions being connected with each other at an inflection point where the direction of the curvature changes sign; and a straight proximal portion. In some preferred embodiments, the distal portion has a radius of curvature between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and the proximal portion has a radius of curvature between about an inner cross-sectional radius of the cannula and about 1 meter; and an angle 01 between a line 13 tangent to the distal portion and to the curved proximal portion at the inflection point and the straight proximal portion is between greater than about 0 degrees to about 180 degrees. The present invention is not limited to the aforementioned delivery device or cannula.

[0050] In some preferred embodiments, the dose delivered is such that radiation retinopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation choroidopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation maculopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation neuropathy is avoided. In some preferred embodiments, the dose delivered is such that cataract is avoided. In some preferred embodiments, the dose delivered is such that choroidal neovascularization is avoided.

[0051] One of the unique and inventive technical features of the present invention is the ability to provide a therapeutically effective dose to the choroid target while avoiding or minimizing damage to other structures of the eye, for example the retina and choriocapillaris . Without wishing to limit the invention to any theory or mechanism, it is believed that the technical feature of the present invention advantageously provides for treatment efficacy while avoiding or minimizing adverse effects of treatment, for example the development of radiation retinopathy, radiation choroidopathy, radiation maculopathy, radiation neuropathy, cataract, and/or choroidal neovascularization. None of the presently known prior references or work has the unique inventive technical feature of the present invention.

[0052] The present invention represents an unexpected advancement in the field of brachytherapy. As will be described herein, prior uses of brachytherapy, and radiotherapy more generally, have taught away from the use of brachytherapy for the treatment of CSCR as implemented in the present invention.

[0053] Radiotherapy (and brachytherapy, as a subfield of radiotherapy) has conventionally been believed to increase , rather than decrease, vascular permeability. Thus, the fact that the present invention decreases vascular permeability through the use of radiation is a surprising result. Radiation has for many decades been taught as increasing vascular permeability: "Research in the 1940' s and 50' s suggested that multiple mechanisms were responsible for increased endothelial barrier permeability following radiation exposure." (Bouten et al. , (2021) Tissue Barriers in Disease, Injury and Regeneration (pp. 43-94) . Elsevier) . Furthermore, radiation exposure has been taught by the prior art to "destabiliz [e] [the] endothelial barrier, increasing vascular permeability, and altering vesicular trafficking." (Bouten et al. , 2021) . These effects of radiation have been observed in vivo in "a wide variety of animal models" and in vitro. (Bouten et al. , 2021) . In in vivo rabbit models, radiation has been taught as increasing "capillary permeabilization" in a localized manner. (Bouten et . al, 2021) .

[0054] Furthermore, this phenomenon has previously been believed to apply to multiple types of radiation at multiple levels of intensity, exposure, or dose. " [C] comparisons of different types of radiation suggest that there is consistency in the effects of radiation on vasculature in response, towards increased vascular permeability, to different energies." (Bouten et al. 2021)

[0055] Furthermore, the relationship between radiation exposure and increased vascular permeability has been reported even at relatively low levels of radiation exposure. "Several studies have demonstrated that vascular permeability increases immediately after irradiation with doses as low as 2 Gy" (Lee, C. G. , et al. (2021) , Journal of Radiation Research, 62 (5) , 856-860) . Therefore, the fact that even the low and controlled radiation doses delivered by the present invention do not increase vascular permeability, but rather decrease it, is nevertheless unexpected. In other words, that the present invention uses radiation (even at low doses) to decrease vascular permeability is an unexpected and surprising result not taught by the prior art. In fact, the prior art teaches away from using even low doses of radiation to decrease vascular permeability, since the prior art teaches that even low doses of radiation increase vascular permeability. In contrast, the present invention surprisingly produces a reduction in vascular permeability via the use of low and well-controlled doses of radiation .

[0056] More recent research has illuminated the molecular mechanisms that underlie the general tendency of radiation to increase vascular permeability. "A common finding from radiation in vitro studies of the endothelial barrier is the reduction in levels of proteins required for endothelial cell-cell contacts." (Bouten et al. , 2021) "Our results suggest a mechanism of irradiation-induced increased permeability... based on the activation of ADAM10 and the subsequent change of endothelial permeability through the degradation and internalization of VE- cadherin . " (Kouam, P. N. , et al. (2019) . BMC Cancer, 19 (1) , 958) . Furthermore, research has identified that radiation levels even as low as 5 Gy gamma radiation or photon-based radiation induces reduction of PECAM-1, an endothelial cell adhesion molecule that is required for endothelial cell-cell adhesion. (Bouten et al. , 2021) Other research found that "vascular permeability increases immediately after irradiation with doses as low as 2 Gy." (Lee et al. , 2021) [0057] Human blood vessels have been found to exhibit increased permeability after exposure of the endothelial layer to ionizing radiation. Furthermore, this relationship has been found to apply to macromolecules of varying sizes, and to be dose-dependent. This has been correlated with decreased amounts of two junction proteins, one of which was VE-cadherin. VE-cadherin was cleaved by ADAM10 in a radiation dose-dependent manner, which appears to be mediated at least in part by intracellular calcium release. Inhibition of ADAMIO rescued radiation-induced permeability (Kabacik, S. et al. (2017) . Oncotarget, 8 (47) , 82049-82063) .

[0058] Further research has identified "at least two mechanisms" that cause "radiation-induced endothelial permeability," " (1) the regulation of levels of cell-cell contact proteins and (2) the increased contractility of endothelial cells" (Bouten et al. , 2021) . Other mechanisms of radiation-induced permeability changes may be due to due to changes in non- paracellular routes, including changes to: osmotically-based passive transporters (e.g., decreased expression of aquaporin 1) , tissue plasminogen activator (which converts plasminogen to plasmin, which in turn breaks down blood clots) , and vascular cell adhesion protein 1 (VCAM1, a protein involved in leukocyte extravasation) . In general, these alterations constitute changes in gene expression that typically involve "reduced adhesion and altered molecule transport." (Bouten et al., 2021)

[0059] The clinical use of coronary brachytherapy directly teaches away from the use of brachytherapy as used in the present invention. Coronary brachytherapy is used in conjunction with coronary angioplasty, and operates on the principle that, in short, radiation delivered to a blood vessel will prevent thickening of the vessel' s wall.

[0060] Atherosclerosis is the formation of fatty plaques in the lumen of arteries, which reduces the area of the lumen, inhibiting blood flow and oxygen delivery to tissues (Nath, R. , et al. (1999) , Med. Phys. , 26: 119-152) . Plaque formation eventually causes smooth muscle cell proliferation, accompanied by collagen and elastin proliferation. In turn, fibrous plaques begin to form which contain lipids, necrotic cells, and collagen. These lesions calcify, causing platelet aggregation, a reduction in blood flow, and formation of a thrombosis, which, particularly if located in the heart, may cause myocardial ischemia or myocardial infarction. (Nath, R., et al. (1999) ) [0061] Percutaneous transluminal angioplasty ("angioplasty") is a procedure intended to break up these plaques, therefore restoring blood flow and preventing myocardial ischemia and/or myocardial infarction. The primary goal of angioplasty is to reestablish a stable lumen with a diameter similar to a normal, healthy artery. Angioplasty is a practice well-known in the art that can be accomplished using a variety of devices and techniques. Described herein in gross detail as an exemplary form of angioplasty is balloon angioplasty. A catheter on a guidewire is introduced into an artery (typically the femoral artery or brachial artery) , and advanced with the aid of imaging to the target artery, usually a coronary artery. The angioplasty device (for example, a balloon angioplasty device) is then inserted and guided via the guidewire to the site of the target lesion to be treated. The angioplasty device (e.g., a balloon angioplasty device) is then used to treat the target lesion by, for example, inflating the balloon within the arterial lumen. Use of the device (e.g. , inflation of the balloon) is intended to increase the diameter of the artery and break up plaques in the target lesion. Physical inflation of the balloon breaks up plaques, and stretches (and often ruptures) the tissues of the vessel lumen, typically the internal elastic lamina. Tissue fissures may extend into the medial layer of the vessel. (Nath, R. , et al. (1999) ) [0062] Following the angioplasty procedure, restenosis (e.g. , re-narrowing) of the vessel is a common and therapeutically undesirable occurrence. Restenosis is believed to involve three separate mechanisms: early recoil, neointimal hyperplasia, and late contraction. Early recoil is simply the elastic recoil that occurs after overstretching of the artery due to stretching produced by the angioplasty procedure itself (e.g. , as caused by inflation of an angioplasty balloon within the arterial lumen) . Intimal proliferation is the result of new tissue growth which proliferates to fill in fissures in the vessel wall produced by the stretching trauma of the angioplasty procedure. Often, this tissue proliferation may occur to the extent that the vessel is severely re-obstructed. Late contraction resembles wound contracture, and is sometimes referred to as remodeling. It essentially involves healed tissues becoming contracted such that the circumference of the vessel is smaller after the procedure than it was before the procedure.

[0063] Intimal hyperplasia (the second mechanism of restenosis) is particularly problematic, with excessive neointimal hyperplasia causing clinically symptomatic restenosis in three to six months in roughly 40% of patients. (Nath, R., et al. (1999) )

[0064] Thus, there exists a strong need to minimize intimal hyperplasia following angioplasty. This is the primary goal of coronary brachytherapy. Following angioplasty, radioactive sources, often beta or gamma emitters, are introduced inside the vessel and used to irradiate the treatment site. (Nath, R. , et al. (1999) ) Studies, both clinical and those in animal models, have confirmed that coronary brachytherapy decreases neointimal hyperplasia following angioplasty. (Nath, R., et al. (1999) ) This discovery followed the hypothesis that "intracoronary irradiation may reduce vascular smooth muscle proliferation and neointimal proliferation after a balloon overstretch procedure, which could prevent or reduce in-stent restenosis." (Ohri, N. , et al. (2015) . Advances in radiation oncology, 1 (1) , 4-9) Indeed, studies in porcine models found that "intracoronary radiation primarily inhibits the first wave of cell proliferation in the vessel wall and demonstrates a favorable effect on late remodeling by preventing adventitial fibrosis at the injury site." (Waksman, R. , et al. (1997) . Circulation, 96 (6) , 1944-1952.

[0065] Conversely, the present invention uses radiation to increase proliferation of certain cells in blood vessel walls, thereby decreasing the permeability of those vessels. This is in contrast to the prior art, which teaches that radiation, even at low doses, decreases cellular proliferation, including by decreasing proliferation of cells in vessel walls (e.g. , including by decreasing intimal hyperplasia) .

[0066] In contrast to this established understanding of radiation' s effects on cellular proliferation, the present invention utilizes radiation to increase cellular proliferation of cells in choroidal vessel walls, thus decreasing the permeability of these vessels. Choroidal vessels in a patient with chronic serous chorioretinopathy are thereby made less permeable, reducing the amount of fluid they leak. As a result, less fluid accumulates under the retina, which resolves the underlying pathophysiological cause of CSCR, thus treating CSCR by stopping the disease process which causes it.

[0067] Without wishing to limit the present invention to any theory or mechanism, it is believed that an advantage of the present invention over previous approaches is that the present invention is capable of increasing intimal proliferation of large choroidal vessels while simultaneously minimizing damage to smaller blood vessels, especially those of the choriocapillaris . Other approaches have shown to cause damage to smaller, more delicate vessels, perhaps most importantly those of the choriocapillaris . Attenuation of the choriocapillaris is often an inherent part of the pathophysiological process of CSCR. Therefore, while it is always desirable to avoid unnecessary damage to the choriocapillaris, doing so is especially important in CSCR, given that the choriocapillaris is often compromised by the disease state itself.

[0068] Smaller vessels are often more sensitive to radiation than larger vessels. For example, studies by Amoaku et al. studied the effects of brachytherapy on choroidal vasculature in the treatment of choroidal melanoma, and found that the among the vessels which experienced radiation-induced atrophy first were vessels of the choriocapillaris. (Amoaku, W. M. K. , et al. (1995) . Eye, 9 (6) , 738-744) Initial changes centered around smaller vessels, with larger vessels experiencing changes later on. Because treatment of CSCR may involve the goal of decreasing the permeability of large choroidal vessels without obliterating the smaller vessels of the choriocapillaris, radiotherapy as previously known in the art would have represented challenges if used for the treatment of CSCR.

[0069] However, the present invention resolves this issue by allowing for the delivery of radiotherapy to the eye such that intimal proliferation of large choroidal vessels is increased, thereby decreasing their permeability, while minimizing damage to the smaller vessels of the choriocapillaris or the retina. In some preferred embodiments, this is accomplished in part by the delivery of an appropriate dose. In some preferred embodiments, the therapeutic dose is from 6 to 18 Gy. As will be described herein, the present invention is not limited to 6 to 18 Gy. Without wishing to limit the present invention to any theory or mechanism, it is believed that the doses in these ranges are such that intimal proliferation of large choroidal vessels is increased while minimizing damages to vessels of the choriocapillaris and other radiosensitive structures of the eye, such as the lens.

[0070] In some preferred embodiments, the present invention features the use of specialized delivery devices such as but not limited to those described in US Patent Application No: 10/836, 140; US Patent Application No: 12/350, 079; US Patent Application No: 12/497, 644; US Patent Application No: 13/111, 765; US Patent Application No: 13/111, 780; US Patent Application No: 13/742, 823; US Patent Application No: 13/872, 941; US Patent Application No: 13/953, 528; US Patent Application No: 14/011, 516; US Patent Application No: 14/486, 401; US Patent Application No: 14/687,784; US Patent Application No: 15/871, 756; US Patent Application No: 15/023, 196; US Patent Application No: 15/004, 538; US Patent Application No: 15/628, 952; US Patent Application No: 16/015, 892; US Patent Application No: 16/009, 646; U.S. Design Application No. 29/332, 021; U.S. Design Application No. 29/332, 028; U.S. Design Application No. 29/332, 032; U.S. Design Application No. 29/332, 040; U.S. Design Application No. 29/368, 499; U.S. Design Application No. 29/368, 501; U.S. Design Application No. 29/391, 557; U.S. Design Application No. 29/391, 558; U.S. Design Application No. 29/391, 559; U.S. Design Application No. 29/391, 561; U.S. Design Application No. 29/564,244; U.S. Design Application No. 29/564,247; U.S. Design Application No. 29/564,249; U.S. Design Application No. 29/576, 148; U.S. Design Application No. 29/576, 159; PCT Application No: PCT/US2009 / 030343 ; PCT Application No: PCT/US2010 / 54958 ; PCT Application No: PCT/US2014 / 56135 ; PCT Application No: PCT/US2016 / 68391 , the specifications of which are incorporated herein in their entirety by reference. Using a specialized device can allow for delivery of an accurate and appropriate dose to a well-defined target area of the eye. In some preferred embodiments, the present invention may therefore minimize the risk associated with any one or more of the following adverse effects associated with radiotherapy: radiation retinopathy, radiation choroidopathy, radiation maculopathy, radiation neuropathy, cataract, and choroidal neovascularization. In some preferred embodiments the present invention may minimize the risk associated with other adverse effects associated with radiotherapy, especially those associated with delivery of excessive doses of radiation.

[0071] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.

[0072] The above and other elements, features, steps, characteristics and advantages of the present invention will become more apparent from the following detailed description of the preferred embodiments with reference to the attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0073] The features and advantages of preferred embodiments of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:

[0074] FIG. 1 shows a depiction of exponential decline in radiation dose with depth from the device. Graph showing exponential decline of the dose of radiation with increasing depth from the device.

[0075] FIG. 2 shows doses of radiation delivered at different depths from the scleral surface (device-sclera interface) . Dose = Dn exp[- 0.846 (d- dn) ] , where the depth of interest is d. Dn is the dose at the depth dn which is the normalization depth (or treatment depth) [0076] FIG. 3 shows that in a normal eye, the dose of radiation delivered at the sclera-choroid interface is 12.4 Gy. The dose is 10 Gy at the interface of large choroidal vessels and medium vessels/ chor iocapillar is .

[0077] FIG. 4 shows that in an eye with central serous chorioretinopathy (CSCR) , the dose of radiation delivered at the sclera-choroid interface would be less than 12.4 Gy, considering the increased scleral thickness in CSCR. The dose of radiation at the interface of large choroidal vessels and medium vessels/choriocapillaris will be 8 Gy because of the increased thickness of the large choroidal vessels layer.

[0078] FIG. 5 shows an episcleral brachytherapy device introduced via sub-Tenon route to deliver radiation to a choroidal neovascular complex through the sclera.

[0079] FIG. 6 shows a non-limiting example of a cannula/delivery device.

[0080] FIG. 7A shows a non-limiting example of a cannula/delivery device.

[0081] FIG. 7B shows a detailed view of the radius of curvature of a portion of a cannula.

[0082] FIG. 7C shows a detailed view of the radius of curvature of a portion of a cannula.

[0083] FIG. 7D shows a detailed view of the relationship between the straight portion of the cannula and the distal and proximal portions of a cannula.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] The present invention features radionuclide brachytherapy sources (RBS) for applying radiation to a target area, for example for treating chronic serous chorioretinopathy (CSCR) . Brachytherapy for Central Serous Chorioretinopathy

[0085] The present invention may be used to provide low dose radiation via episcleral brachytherapy in refractory cases of central serous chorioretinopathy (CSCR) .

[0086] The pathogenesis of CSCR involves dilatation and hyperpermeability of large choroidal vessels. Low dose radiation can induce intimal proliferation in large choroidal vessels and decrease their hyperpermeability. Concerns about the use of brachytherapy in CSCR include damage to the choriocapillaris or the retinal vessels. This can be addressed with the use of a specialized device through which a very precise and appropriate dose can be delivered. The dose of the radiation delivered decreases exponentially at a depth of approximately 0.5-1.5 mm from the device-sclera interface.

[0087] Dose titration of the radiation is key to minimize the damage to the choriocapillaris and avoid radiation retinopathy, radiation maculopathy, radiation neuropathy, and cataract. Specialized devices for episcleral brachytherapy such as the SalutarisMD promise additional safety and ease of performing the procedure, thus making it more practical.

[0088] Central serous chorioretinopathy (CSCR) is a disease characterized by the neurosensory detachment with or without pigment epithelial detachment due to dysfunctional retinal pigment epithelium (RPE) and hyperpermeable choroid. Choroidal features of CSCR are choriocapillaris attenuation and dilatation of large vessels of the choroid. Whether dilated large vessels of the choroid cause a mechanical compression of the choriocapillaris layer, or atrophy of the choriocapillaris is the primary event, is still debatable.

[0089] The acute, isolated event of CSCR mostly resolves spontaneously, but the chronic variant of the disease, which is also known as diffuse retinal pigment epitheliopathy , is progressive and can lead to severe bilateral visual impairment. Many treatment options have been tried for this form of the disease and so far photodynamic therapy (PDT) is the treatment of choice. However, PDT shows limited success in 30-40% of cases with risk of complications including vision loss. Limited availability of verteporfin and laser systems in many countries and an off-label indication are making PDT as a vanishing treatment option. The limited role of eplerenone, as reported by the VICI trial, further limits the treatment options for this debilitating disease.

[0090] The prime target of the present invention is the hyperpermeable choroidal vasculature. Concerns associated with plaque radiotherapy include platelet aggregates, development of choroidal neovascularization (CNV) , radiation maculopathy, optic neuropathy, and radiation chorioretinopathy.

[0091] Radionuclide strontium-90 (90Sr) emits only high energy beta particles which have highest attenuation in biological tissues making it more suitable for ocular use. Yttrium-90 (90Y) is the daughter product of 90Sr after beta decay and emits more energetic beta particles.

[0092] Stereotactic radiotherapy is another method of radiotherapy that provides stereotactic application of low energy X-ray to the CNV using three highly collimated beams that cross the inferior sclera to overlap at the macula. Unlike epimacular brachytherapy, this outpatient-based radiotherapy does not require vitrectomy and thus is a more practical method of radiotherapy. [0093] An aim of the present invention is to decrease the blood flow through the large choroidal vessels without obliteration of the choriocapillaris . The mechanism of action in this case would likely be due to the effect of radiation on the endothelial cells. The radiation dose can even be reduced further to attain the desired effect of producing intimal proliferation whereby the leakiness stops or is reduced. Unlike the effect on cancer cells where the objective is to create enough deoxyribonucleic acid (DNA) double-strand breaks to induce cell death, in its application for CSCR, the lower radiation dose will cause deposition of collagen around the leaky vessels thus changing their permeability over a period of months.

[0094] When an RBS is placed on or near the sclera, it may be possible for the radiation to affect the large choroidal vessel layer without adversely affecting the choriocapillaris . Referring to FIG. 1, FIG. 2, FIG. 3, and FIG. 4, the dose of the radiation is an exponential function for depths from approximately 0.5 mm to 1.5 mm, where the depth is measured from the front face of the device (the device-sclera interface has a depth of zero) . Dose = D _n exp[- 0.846 (d-d _n ) ] , where the depth of interest is d. D _n is the dose at the depth d _n which is the normalization depth (or treatment depth) . Studies have shown choroidal thickness at the macula is around 256 Im of which 2041m is occupied by the large vessels (Haller layer) and 521m by the choriocapillaris/Satt ler layer in normal eyes. In CSCR, total choroidal thickness is increased (394 pm) because of increased thickness of the large vessel layer (307 pm) . Scleral thickness at the posterior pole is around 1 mm. Although scleral thickness at the posterior pole has not been measured in eyes with CSCR, scleral thickness 6 mm posterior to the scleral spur, as measured on anterior segment optical coherence tomography, is thicker than in normal eyes and an increased scleral thickness has been implicated in the pathogenesis of CSCR.

[0095] The typical human choroid is generally between 0.5 mm to 1.5 mm deep in the structure of the eye, as measured from the posterior surface of the eye. The target is the choroid, e.g. , the approximate median depth of the choroid. The present invention describes delivering a therapeutic dose to a particular range of depths (as measured from the interface of the sclera and delivery device) . In some preferred embodiments, the depth ranges from 0.5 mm to 2.0 mm. In some preferred embodiments, the depth ranges from 0.75 mm to 2.0 mm. In some preferred embodiments, the depth ranges from 1.0 mm to 2.0 mm. In some preferred embodiments, the depth ranges from 0.5 mm to 1.5 mm. The present invention is not limited to the aforementioned depth ranges relevant to the therapeutic dose delivery.

[0096] The choroid is within the range of depths to which the therapeutic dose (s) is delivered, e.g. , in some preferred embodiments, the depth of the target (e.g. , median depth of the choroid) is 1.25 mm from the interface of the sclera and delivery device, therefore the target receives the therapeutic dose. In some preferred embodiments, the choroid target is from 0.5 to 2 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 0.75 to 1.5 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 0.5 to 2 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 1 to 1.5 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 0.75 to 1.75 mm from the interface of the sclera and delivery device.

[0097] A radiation dose delivered to the choriocapillaris of less than 10 Gy may induce intimal proliferation in larger choroidal vessels, thus reducing hyperpermeability of these vessels, while also minimizing damage to the choriocapillaris and other more radiosensitive structures of the eye.

[0098] A novel episcleral brachytherapy device has been introduced by Salutaris Medical Devices, Inc. (SalutarisMD) to treat wet AMD with an accurate therapeutic dose. It employs a 90Sr/90Y source RBS encapsulated in a stainless steel holder which is loaded into the distal end of the applicator' s curved cannula. The device is introduced through the retrobulbar sub-Tenon route and radiation is delivered through the sclera to the CNV lesion over a matter of minutes (see FIG. 5) . A clinical trial to assess the safety and feasibility of the device in patients with wet AMD has been started and is expected to complete in 2022.

[0099] Dose titration of the radiation is key to minimize the damage to the choriocapillaris and other radiosensitive structures of the eye, and to avoid radiation retinopathy, radiation maculopathy, radiation neuropathy, and cataract. Specialized devices for episcleral brachytherapy such as the SalutarisMD may be used in conjunction with the present invention in order to provide additional safety and ease of performing a procedure utilizing the present invention, thus making it more practical.

RBS systems for Chronic Serous Chorioretinopathy

[0100] The present invention may be used to treat chronic serous chorioretinopathy (CSCR) . For example, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, the method comprising inserting said cannula into a potential space under a Tenon' s capsule of the eye, whereby the RBS is positioned over a choroid target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the choroid target. A radioactive therapeutic portion of the RBS is consumed during the method. The RBS may be present in a delivery device, e.g. , in a cannula of a delivery device.

[0101] As previously discussed, in some preferred embodiment, the choroid target is from 0.5 to 2 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 0.75 to 1.5 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 0.5 to 2 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 1 to 1.5 mm from the interface of the sclera and delivery device. In some preferred embodiments, the choroid target is from 0.75 to 1.75 mm from the interface of the sclera and delivery device.

[0102] Without wishing to limit the present invention to any theory or mechanism, the therapeutic doses are generally selected such that intimal proliferation of large choroidal vessels is increased while damage to vessels of the choriocapillaris and other radiosensitive structures of the eye, such as the lens, are minimized. In general, it is desirable to avoid excessive radiation exposure to structures other than the target (e.g. , large choroidal vessels) . Other radiosensitive structures that it may be desirable to avoid radiation exposure to include the lens, the choriocapillaris, the retina, and retinal blood vessels.

[0103] In some preferred embodiments, the therapeutic dose is from 6 to 18 Gy. In some preferred embodiments the therapeutic dose is 6-8 Gy. In some preferred embodiments the therapeutic dose is 6-10 Gy. In some preferred embodiments the therapeutic dose is 6-12 Gy. In some preferred embodiments the therapeutic dose is 6-

16 Gy. In some preferred embodiments the therapeutic dose is 8-10

Gy. In some preferred embodiments the therapeutic dose is 8-12 Gy.

In some preferred embodiments the therapeutic dose is 8-16 Gy. In some preferred embodiments the therapeutic dose is 8-18 Gy. In some preferred embodiments the therapeutic dose is 10-12 Gy. In some preferred embodiments the therapeutic dose is 10-14 Gy. In some preferred embodiments the therapeutic dose is 10-18 Gy . In some preferred embodiments the therapeutic dose is 12-16 Gy. In some preferred embodiments the therapeutic dose is 12-18 Gy. In some preferred embodiments the therapeutic dose is 14-18 Gy.

[0104] The therapeutic dose is delivered to a particular depth or range of depths, e.g. , as measured from the interface of the sclera and the delivery device. For example, in some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 2 mm is from 8-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.75 mm to 1.75 mm is from 8-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 1 mm to 1.5 mm is from 8-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 6-12 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-18 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-16 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-14 Gy. In some preferred embodiments, the therapeutic dose delivered to a depth from 0.5 mm to 1.25 mm is from 8-12 Gy.

[0105] In some preferred embodiments, the therapeutic dose is calculated based on the thickness of the choroid target. In some preferred embodiments, a thicker choroid target may dictate that a larger therapeutic dose is used. In some preferred embodiments, a thicker choroid target may dictate that a smaller therapeutic dose is used.

[0106] In some preferred embodiments, the thickness of the choroid target is measured using imaging. In some preferred embodiments, the imaging may comprise optical coherence tomography (OCT) , optical coherence tomography (OCT) using enhanced depth imaging (EDI) , Spectral Domain Optical Coherence Tomography (SD- OCT) , Swept Source Optical Coherence Tomography (SS-OCT) , or Topcon Deep Range Imaging OCT.

[0107] In some preferred embodiments, the retina is exposed to less than 6 Gy. In some preferred embodiments, the retina is exposed to less than 8 Gy. In some preferred embodiments, a choriocapillaris is exposed to less than 8 Gy. In some preferred embodiments, a choriocapillaris is exposed to less than 10 Gy. In some preferred embodiments, an interface of large choroidal vessels and a choriocapillaris is exposed to less than 10 Gy. In some preferred embodiments, an interface of large choroidal vessels and a choriocapillaris is exposed to less than 12 Gy. In some preferred embodiments, the retina is exposed to less radiation than the choroid target. In some preferred embodiments, a choriocapillaris is exposed to less radiation than the choroid target. In some preferred embodiments, a lens is exposed to less radiation than the choroid target. In some preferred embodiments, a retinal blood vessel is exposed to less radiation than the choroid target .

[0108] The dose is delivered to the choroid target in a period of time, e.g. , a dwell time. In some preferred embodiments, the dwell time is from 5 seconds to 10 minutes. In some preferred embodiments, the dwell time is from 5 seconds to 15 second. In some preferred embodiments, the dwell time is from 5 seconds to 30 seconds. In some preferred embodiments, the dwell time is from 5 seconds to 45 seconds. In some preferred embodiments, the dwell time is from 5 seconds to 1 minute. In some preferred embodiments, the dwell time is from 5 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 15 seconds to 30 seconds. In some preferred embodiments, the dwell time is from 15 seconds to 1 minute. In some preferred embodiments, the dwell time is from 15 seconds to 90 seconds. In some preferred embodiments, the dwell time is from 15 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 30 seconds to 1 minute. In some preferred embodiments, the dwell time is from 1 minute to 90 seconds. In some preferred embodiments, the dwell time is from 1 minute to 2 minutes. In some preferred embodiments, the dwell time is from 90 seconds to 2 minutes. In some preferred embodiments, the dwell time is from 2 to 4 minutes. In some preferred embodiments, the dwell time is from 4 to 6 minutes. In some preferred embodiments, the dwell time is from 6 to 8 minutes. In some preferred embodiments, the dwell time is from 8 to 10 minutes. In some preferred embodiments the dwell time is from 5 to 10 minutes. In some preferred embodiments, the dwell time is greater than 10 minutes.

[0109] In some preferred embodiments the RBS delivers radiation to an irradiated area. In some preferred embodiments, the diameter of the irradiated area is up to 8 millimeters. In some preferred embodiments, the diameter of the irradiated area is up to 12 millimeters. In some preferred embodiments, the diameter of the irradiated area is 3-5 millimeters. In some preferred embodiments, the diameter of the irradiated area is 1-3 millimeters. In some preferred embodiments, the diameter of the irradiated area is 5-7 millimeters. In some preferred embodiments, the diameter of the irradiated area is 7-9 millimeters. In some preferred embodiments, the diameter of the irradiated area is 9-12 millimeters.

[0110] In some preferred embodiments, the RBS is a source of ionizing radiation. In some preferred embodiments, the RBS is a source of particle radiation. In some preferred embodiments, the RBS is a source of beta radiation. In some preferred embodiments, the RBS is a source of alpha radiation. In some preferred embodiments, the RBS is a source of neutron radiation. In some preferred embodiments, the RBS is a source of X-ray radiation. In some preferred embodiments, the RBS is a source of other electromagnetic radiation. In some preferred embodiments, the RBS is a source of multiple types of radiation.

[0111] The present invention also features a method of reducing hyperpermeability of large choroidal vessels in an eye of a patient in need thereof with central serous chorioretinopathy. In some preferred embodiments, the method comprises inserting a cannula into a potential space under a Tenon' s capsule of the eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a choroid target, and wherein a therapeutic dose of radiation is delivered to the choroid target. In some preferred embodiments, a reduction in hyperpermeability will result in less fluid accumulation under the retina, thus treating CSCR.

[0112] The present invention also features a method of increasing collagen deposition associated with large choroidal vessels in an eye of a patient in need thereof with central serous chorioretinopathy. In some preferred embodiments, the method comprises inserting a cannula into a potential space under a Tenon' s capsule of the eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a choroid target, and wherein a therapeutic dose of radiation is delivered to the choroid target. In some preferred embodiments, an increase in collagen deposition associated with large choroidal vessels will cause a reduction in hyperpermeability that will result in less fluid accumulation under the retina, thus treating CSCR.

[0113] The present invention also features a method of treating central serous chorioretinopathy in a patient in need thereof. In some preferred embodiments, the method comprises inserting a cannula into a potential space under a Tenon' s capsule of an eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a choroid target, and wherein a therapeutic dose of radiation is delivered to the choroid target. In some preferred embodiments, treating CSCR may be accomplished by inducing a reduction in hyperpermeability of large choroidal vessels and/or increasing collagen deposition associated with large choroidal vessels and/or reducing fluid accumulation under the retina.

[0114] In some preferred embodiments, the dose delivered is such that radiation retinopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation choroidopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation maculopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation neuropathy is avoided. In some preferred embodiments, the dose delivered is such that cataract is avoided. In some preferred embodiments, the dose delivered is such that choroidal neovascularization is avoided. In some preferred embodiments, the dose delivered is such that other adverse events of radiation therapy are avoided.

[0115] The therapeutic dose to be administered may be calculated a priori before any treatment course (or a portion thereof) is delivered.

[0116] Referring to the methods herein, the therapeutic dose to be administered, e.g. , a treatment course, may be fractionated (e.g., divided and delivered) over a number of sessions. For example, in some preferred embodiments, the therapeutic dose is fractionated over at least 2 sessions. In some preferred embodiments, the therapeutic dose is fractionated over 2 sessions. In some preferred embodiments, the therapeutic dose is fractionated over 3 sessions. In some preferred embodiments, the therapeutic dose is fractionated over 4 sessions. In some preferred embodiments, the therapeutic dose is fractionated over more than 4 sessions. In some preferred embodiments, the sessions are divided into a time frame of 1 week. In some preferred embodiments, the sessions are divided into a time frame of 2 weeks. In some preferred embodiments, the sessions are divided into a time frame of 3 weeks. In some preferred embodiments, the sessions are divided into a time frame of 4 weeks. In some preferred embodiments, the sessions are separated by 1 to 7 days. In some preferred embodiments, the sessions are separated by 5 to 10 days. In some preferred embodiments, the sessions are separated by 5 to 14 days. In some preferred embodiments, the sessions are separated by 5 to 21 days .

[0117] In some preferred embodiments, the patient is reassessed after a period of time following the first treatment course to determine if the patient needs a second treatment course. The patient may also be reassessed after additional treatment courses as well, for example, in some preferred embodiments, the patient is reassessed following a second treatment course to determine if the patient needs a third treatment course. In some preferred embodiments, the time frame between two particular treatment courses (e.g. , a first treatment course and a second treatment course, a second treatment course and a third treatment course, etc.) is 3-12 months. In some preferred embodiments, the time frame between two particular treatment courses is 3-6 months. In some preferred embodiments, the time frame between two particular treatment courses is 6 to 12 months. In some preferred embodiments, the time frame between two particular treatment courses is 3 to 24 months. In some preferred embodiments, the time frame between two particular treatment courses is 3 to 36 months. In some preferred embodiments, the time frame between two particular treatment courses is greater than a year. In some preferred embodiments, the time frame between two particular treatment courses is greater than 2 years. In some preferred embodiments, the time frame between two particular treatment courses is greater than 3 years.

[0118] As described above, the first treatment course may be fractionated, e.g. , divided and delivered over the course of at least 2 sessions. Likewise, in some preferred embodiments, the second (or third or subsequent courses) may also be fractionated over at least 2 sessions.

[0119] In some preferred embodiments, the RBS is contained within a cannula. In some preferred embodiments the cannula is part of a delivery device, wherein the delivery device comprises: a cannula comprising a curved distal portion adapted for placement around a portion of a globe of an eye; a curved proximal portion, the curved distal portion and the curved proximal portions being connected with each other at an inflection point where the direction of the curvature changes sign; and a straight proximal portion, wherein (a) the distal portion has a radius of curvature between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and (b) the proximal portion has a radius of curvature between about an inner cross-sectional radius of the cannula and about 1 meter; and wherein an angle 91 between a line 13 tangent to the distal portion and to the curved proximal portion at the inflection point and the straight proximal portion is between greater than about 0 degrees to about 180 degrees. The present application incorporates the following patent applications in their entirety herein by reference: In some preferred embodiments, the present invention features the use of specialized delivery devices such as but not limited to those described in US Patent Application No: 10/836, 140; US Patent Application No: 12/350, 079; US Patent Application No: 12/497, 644; US Patent Application No: 13/111, 765; US Patent Application No: 13/111, 780; US Patent Application No: 13/742, 823; US Patent Application No: 13/872, 941; US Patent Application No: 13/953, 528; US Patent Application No: 14/011, 516; US Patent Application No: 14/486, 401; US Patent Application No: 14/687, 784; US Patent Application No: 15/871,756; US Patent Application No: 15/023, 196; US Patent Application No: 15/004, 538; US Patent Application No: 15/628, 952; US Patent Application No: 16/015, 892; US Patent Application No: 16/009, 646; U.S. Design Application No. 29/332, 021; U.S. Design Application No. 29/332, 028; U.S. Design Application No. 29/332, 032; U.S. Design Application No. 29/332, 040; U.S. Design Application No. 29/368, 499; U.S. Design Application No. 29/368, 501; U.S. Design Application No. 29/391, 557; U.S. Design Application No. 29/391, 558; U.S. Design Application No. 29/391, 559; U.S. Design Application No. 29/391, 561; U.S. Design Application No. 29/564,244; U.S. Design Application No. 29/564,247; U.S. Design Application No. 29/564,249; U.S. Design Application No. 29/576, 148; U.S. Design Application No. 29/576, 159; PCT Application No: PCT/US2009/030343; PCT Application No: PCT/US2010/54958; PCT Application No: PCT/US2014/56135; PCT Application No: PCT/US2016 / 68391. FIG. 5, FIG. 6, FIG. 7A, FIG. 7B, FIG. 7C, and FIG. 7D show non-limiting examples of cannulas. For example, in some preferred embodiments, the system comprises a cannula (e.g. , as part of a delivery device) . In some preferred embodiments, the cannula (100) comprises a curved distal portion (110) adapted for placement around a portion of a globe of an eye; a curved proximal portion (120) , the curved distal portion and the curved proximal portions being connected with each other at an inflection point (130) where the direction of the curvature changes sign. In some preferred embodiments, the cannula comprises a straight proximal portion. In some preferred embodiments, the distal portion has a radius of curvature (180) between about 9 mm to 15 mm and an arc length between about 25 mm to 35 mm; and the proximal portion has a radius of curvature (190) between about an inner cross-sectional radius of the cannula and about 1 meter; and the angle 0i (425) between a line (420) tangent to the distal portion and to the curved proximal portion at the inflection point and the straight proximal portion is between greater than about 0 degrees to about 180 degrees.

[0120] In some preferred embodiments, the present invention may be used to treat macular edema. In some preferred embodiments, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein said RBS is present in a cannula of a delivery device, the method comprising inserting said cannula into a potential space under a Tenon' s capsule of the eye, whereby the RBS is positioned over a target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the target, wherein a radioactive therapeutic portion of the RBS is consumed during the method. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0121] In some preferred embodiments, the present invention may be used to treat diabetic retinopathy (DR) . In some preferred embodiments, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein said RBS is present in a cannula of a delivery device, the method comprising inserting said cannula into a potential space under a Tenon' s capsule of the eye, whereby the RBS is positioned over a target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the target, wherein a radioactive therapeutic portion of the RBS is consumed during the method. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0122] In some preferred embodiments, the present invention may be used to treat central macular edema (CME) . In some preferred embodiments, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein said RBS is present in a cannula of a delivery device, the method comprising inserting said cannula into a potential space under a Tenon's capsule of the eye, whereby the RBS is positioned over a target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the target, wherein a radioactive therapeutic portion of the RBS is consumed during the method. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0123] In some preferred embodiments, the present invention may be used to treat macular edema (ME) secondary to central retinal vein occlusion (CRVO) . In some preferred embodiments, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein said RBS is present in a cannula of a delivery device, the method comprising inserting said cannula into a potential space under a Tenon' s capsule of the eye, whereby the RBS is positioned over a target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the target, wherein a radioactive therapeutic portion of the RBS is consumed during the method. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid. [0124] In some preferred embodiments, the present invention may be used to treat macular edema (ME) secondary to branch retinal vein occlusion (BRVO) . In some preferred embodiments, the present invention features a radionuclide brachytherapy source (RBS) for use in a method of irradiating a target of an eye, wherein said RBS is present in a cannula of a delivery device, the method comprising inserting said cannula into a potential space under a Tenon' s capsule of the eye, whereby the RBS is positioned over a target at the back of the eye, wherein a therapeutic dose of radiation is delivered to the target, wherein a radioactive therapeutic portion of the RBS is consumed during the method. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0125] In some preferred embodiments, the present invention features a method of reducing hyperpermeability of large choroidal vessels in an eye of a patient in need thereof with at least one condition selected from the following: macular edema, diabetic retinopathy, diabetic macular edema, cystoid macular edema, macular edema secondary to central retinal vein occlusion, or macular edema secondary to branch retinal vein occlusion, said method comprising inserting a cannula into a potential space under a Tenon' s capsule of the eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a target, and wherein a therapeutic dose of radiation is delivered to the target. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0126] In some preferred embodiments, the present invention features a method of increasing collagen deposition associated with large choroidal vessels in an eye of a patient in need thereof with at least one condition selected from the following: macular edema, diabetic retinopathy, diabetic macular edema, cystoid macular edema, macular edema secondary to central retinal vein occlusion, or macular edema secondary to branch retinal vein occlusion, said method comprising inserting a cannula into a potential space under a Tenon' s capsule of the eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a target, and wherein a therapeutic dose of radiation is delivered to the target. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0127] In some preferred embodiments, the present invention features a method of treating at least one condition selected from the following: macular edema, diabetic retinopathy, diabetic macular edema, cystoid macular edema, macular edema secondary to central retinal vein occlusion, or macular edema secondary to branch retinal vein occlusion in a patient in need thereof, said method comprising inserting a cannula into a potential space under a Tenon' s capsule of an eye of the patient, the cannula having a radionuclide brachytherapy source (RBS) at a treatment position, whereby the RBS is positioned over a target, and wherein a therapeutic dose of radiation is delivered to the target. In some preferred embodiments, the therapeutic dose may range from 6 to 24 Gy. In some preferred embodiments, the target is a blood vessel. In some preferred embodiments, the target is located in the choroid. In some preferred embodiments, the target is located outside of the choroid.

[0128] Referring to the preferred embodiments herein, in some preferred embodiments, the dose delivered is such that radiation retinopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation choroidopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation maculopathy is avoided. In some preferred embodiments, the dose delivered is such that radiation neuropathy is avoided. In some preferred embodiments, the dose delivered is such that cataract is avoided. In some preferred embodiments, the dose delivered is such that choroidal neovascularization is avoided. In some preferred embodiments, the dose delivered is such that adverse effects are avoided.

[0129] As used herein, the term "about" refers to plus or minus 10% of the referenced number.

[0130] Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims . Therefore, the scope of the invention is only to be limited by the following claims. In some preferred embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some preferred embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some preferred embodiments, descriptions of the inventions described herein using the phrase "comprising" includes preferred embodiments that could be described as "consisting essentially of" or "consisting of", and as such the written description requirement for claiming one or more preferred embodiments of the present invention using the phrase "consisting essentially of" or "consisting of" is met. [0131] The reference numbers recited in the below claims are solely for ease of examination of this patent application, and are exemplary, and are not intended in any way to limit the scope of the claims to the particular features having the corresponding reference numbers in the drawings.