WO1996009838A1 - PROCEDE DE TRAITEMENT DE LA DEGENERESCENCE MACULAIRE AU MOYEN DE TGF-$g(b) - Google Patents

PROCEDE DE TRAITEMENT DE LA DEGENERESCENCE MACULAIRE AU MOYEN DE TGF-$g(b) Download PDF

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Publication number
WO1996009838A1
WO1996009838A1 PCT/US1995/011316 US9511316W WO9609838A1 WO 1996009838 A1 WO1996009838 A1 WO 1996009838A1 US 9511316 W US9511316 W US 9511316W WO 9609838 A1 WO9609838 A1 WO 9609838A1
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WIPO (PCT)
Prior art keywords
tgf
retinal
treatment
patients
macular
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PCT/US1995/011316
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English (en)
Inventor
Bert M. Glaser
Bruce B. Pharriss
Ann F. Hanham
George A. Ksander
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Celtrix Pharmaceuticals, Inc.
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Priority to AU35848/95A priority Critical patent/AU3584895A/en
Publication of WO1996009838A1 publication Critical patent/WO1996009838A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]

Definitions

  • This invention is a method for treating a variety of ophthalmic disorders in which wound healing is impaired or requires modulation, including macular holes, macular degeneration, retinal detachment and tears, retinal edema, retinal vascular disorders, retinal neovascularization, wound healing disorders,
  • TGF- ⁇ 2 Transforming Growth Factor- ⁇
  • TGF- ⁇ preferred form of TGF- ⁇ .
  • Other growth factors which have wound healing and neurotrophic effects may also be applied.
  • ophthalmic disorders affect the retina, lens and cornea.
  • retinal disorders include macular holes and degeneration, retinal tears, diabetic retinopathy, and miscellaneous disorders.
  • Important disorders of the lens include cataracts and refractive errors.
  • Important disorders of the cornea include those that are related to corneal defects, including corneal ulcers and wounds and the consequences of dry eye / Sjögren's syndrome. Disorders of the lens and retina are also associated with glaucoma. These are discussed briefly below.
  • the retina is the light-sensitive portion of the eye. Supported by the choroid and retinal pigment cells and found at the posterior of the eye, the retina contains the cones and rods which detect colors. When the rods and cones are excited, they transmit signals which pass through successive neurons in the retina to the optic nerve and finally to the cerebral center, where a "visual picture" is integrated.
  • the macula lutea In the center of the retina is the macula lutea, which is about 1/3 to 1/2 cm in diameter.
  • the macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all
  • the choroid Under the retina are the choroid, a collection of blood vessels embedded within a fibrous tissue, and the deeply pigmented epithelium, which overlays the choroid layer.
  • the choroidal blood vessels provide nutrition to the retina (particularly its visual cells).
  • the retina may tear, form holes and separate from the underlying choroid.
  • macular holes which produce blurred central vision or metamorphopsia.
  • the cause of most macular holes is unknown.
  • trauma, cystic degeneration, and vitreoretinal traction have all been associated with hole formation.
  • Full thickness macular holes also appear following myopic degeneration, laser photocoagulation, lightning strike and pilocarpine administration. There also is a higher frequency of macular holes after cataract extraction.
  • the idiopathic senile macular hole is a
  • retinal vascular and macular diseases which may exhibit voids, tears, or separations in the retina resulting from lack of fibrous or supporting tissue.
  • Age-related macular degeneration is a sight-threatening disorder which occurs in either an atrophic or an exudative form. AMD is the major cause of severe visual loss in United States citizens over the age of 55. Most AMD patients have a build up of deposits within and under the retinal pigment epithelium in the macular region resulting in atrophy of the retina and the retinal pigment epithelium. The retinal pigment cells are long-lived. They scavenge for photoreceptor discs from the rods and cones for years and accumulate
  • photoreceptors decreases, and this may be the basis for macular degeneration.
  • exudative AMD blood vessels grow from the choriocapillaris through defects in Bruch's membrane, and in some cases the underlying retinal pigment epithelium (RPE). Organization of serous or hemorrhagic exudates escaping from these vessels results in fibrous scarring of the macular region with attendant degeneration of the neuroretina and permanent loss of central vision.
  • RPE retinal pigment epithelium
  • the retina may tear or separate from the choroid, and the choroid may rupture, for a wide variety of reasons.
  • tissue separation occurs in such widely disparate conditions as detachment of retina and pigment epithelium, degenerative myopia, as may be evidenced by visible breaks in Bruch's membrane (lacquer cracks), acute retinal necrosis
  • ARN traumatic chorioretinopathies or contusion
  • Purtscher's Retinopathy traumatic chorioretinopathies or contusion
  • retinal disorders include edema and ischemic conditions.
  • Macular and retinal edema are often associated with metabolic illnesses such as diabetes mellitus.
  • Retinal edema is found in a large percentage of individuals who have undergone cataract extraction and other surgical procedures upon the eye. Edema is also found with accelerated or malignant hypertension.
  • Macular edema is a common complication of prolonged inflammation via uveitis, Eales disease, or other diseases. Local edema is associated with multiple cystoid bodies ("cotton bodies”) as a result of AIDS.
  • Retinal ischemia can occur from either choroidal or retinal vascular diseases, such as central or branch retinal vein occlusion, collagen vascular diseases and thrombocytopenic purpura.
  • PDR Proliferative Diabetic Retinopathy
  • the initiating event may be inadequate tissue oxygenation which causes vasodilation. Inadequate oxygenation may occur after the arterial basement membrane has thickened with diabetes-related deposits and because of endothelial cell proliferation, which is associated with pericyte degeneration. Basement membrane thickening and loss of pericytes are believed to result from low insulin and hyperglycemia, two important metabolic abnormalities of diabetes.
  • FGF fibroblast growth factors
  • TGF- ⁇ and ⁇ tumor necrosis factor
  • retinal blood vessels appear to have a unique response to diabetic ischemia, there may be specific retina-derived growth factors.
  • a vitreous protein with a molecular weight of 6200 was found to inhibit PDGF-induced proliferation and thymidine
  • Uveitis refers to inflammation of the uveal tract. It includes ulceris, cyclitis and iridocyclitis and choroiditis and usually occurs with inflammation of additional structures of the eye. These disorder has a variety of causes but is typically treated with systemic steroids, topical steroids or cyclosporin. The disease frequently presents with a chronic inflammation occurring either in the anterior segment (70%) or in the posterior segment (30%) which is complicated by episodes of severe exacerbation that may not be controllable with
  • Cataracts are opacities in what should be perfectly clear lenses. Cataracts interfere with the vision by causing blurred vision, glare, altered color perception and monocular diplopia. They develop in association with a variety of factors, including x-ray exposure and metabolic diseases such as diabetes,
  • Wilson's disease (copper accumulation) and galactosemia. Cataracts may also develop as a side effect of cortisone, methotrexate and nitrogen mustard therapy.
  • the cornea and conjunctiva are vulnerable to damage from pathogenic agents or direct trauma. They are also subject to drying associated with disorders of the tear ducts, exposure to radiant energy (ultraviolet light, sun and welding guns), allergens such as pollen and mold, and infectious agents. Keratoconjunctivitis is an inflammatory
  • keratoconjunctivitis results from exposure to allergans such as pollens. Corneal ulcers may occur if the disorder is allowed to progress.
  • corneal surgery Patients who have undergone corneal surgery are also candidates for ophthalmic healing therapy.
  • Common types of corneal surgery include cataract extraction, with or without lens replacement; corneal transplants, to treat viral infection or penetrating keratoplasty (PKP); glaucoma filtration surgery; and radial keratotomy and other types of surgery to correct refraction.
  • PGP penetrating keratoplasty
  • Cataract incisions are full thickness wounds in the cornea which can be as large as 8 mm in length with conventional intraocular lenses (IOLs) and as small as 3 mm or less with foldable silicone IOLs. These wounds typically heal without difficulty, although they take several months to stabilize and are associated with warpage of the corneal tissues that can lead to permanent astigmatism. Treatment which could speed stabilization of vision and avoid astigmatism would be highly
  • Penetrating keratoplasty (PKP) and corneal transplant are characterized by full-thickness wounds around the entire circumference of the cornea. These wounds tend to remain weak for one or more years.
  • RK Radial keratotomy
  • Fibroblast growth factor is known to be involved in the proliferation of corneal epithelial cells and scleral fibroblasts. TGF- ⁇ is believed to encourage fetal scleral development but effects later in life have not been reported.
  • a method of enhancing healing of corneal epithelial wounds without scarring would help maintain vision after the cornea is wounded. Such predictable healing would be highly beneficial in contributing to a more predictable surgical outcome in RK.
  • Sjögren's syndrome is an immune system disorder which manifests itself in the eyes as conjunctival and corneal dryness (keratoconjunctivitis sicca syndrome) and a gritty sensation in the eyes. This is due to lack of tear resulting from destruction of the lacrimal (or tear) glands by progressive mononuclear cell infiltrate and scarring of the gland. If the cornea is too dry, corneal ulcerations can develop.
  • Neovascularization is a serious complication of a large number of ocular disorders affecting the various tissues of the eye. Neovascularization can lead to blindness. Corneal neovascularization occurs in many conditions and diseases, including trauma, chemical burns and corneal transplantation.
  • Corneal transplantation is successful in many patients because of the absence of blood vessels in the corneal tissue. Because there are no blood vessels in the cornea, the circulating components of the immune system are not exposed to the new cornea and there is normally no problem of host-graft rejection. Induction of neovascularization in the cornea would expose the cornea to the immune system and lead to graft rejection. In addition, when neovascularization has occurred, a subsequent graft is less likely to be successful.
  • Prevention of neovascularization may include the
  • immunosuppressives may inhibit appropriate wound healing in the cornea and interfere with the patient's ability to fight infections. Delayed wound healing leaves the cornea vulnerable to infections for longer periods. Hence, vision-threatening infections can result from current treatments.
  • Neovascularization of the iris can arise as a consequence of diabetic retinopathy, venous occlusion, ocular tumors and retinal detachment.
  • neovascularization process and its attendant scarring can result in glaucoma and blindness. Most commonly, this condition is treated with laser therapy to cauterize the blood vessels; however, laser treatment itself has the attendant risk of causing additional scarring.
  • Retinal and intravitreal neovascularization occurs in a wide range of disorders including diabetic retinopathy, vein occlusions, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia and trauma.
  • Subretinal pigment epithelial (RPE) and subretinal neovascularization are common, yet very severe, disorders of the eye.
  • the growth of new blood vessels interferes with the normal anatomy of the visual and pigmentary cells in the eye, leading to severe visual loss.
  • the new blood vessels leak fluid and blood under the macula causing marked distortion and loss of vision.
  • these blood vessels develop in the avascular foveal region of the eye, the result is central visual loss and legal blindness.
  • neovascularization are unknown; however, this disease most often affects patients over the age of 50 years old, who may or may not have a family history of subfoveal neovascularization.
  • the visual loss is usually
  • neovascularization have a poor prognosis.
  • visual acuity tends to decrease gradually to a mean of 20/400 (Macular Photocoagulation Study Group, 1991).
  • Choroidal neovascularization is caused by such retinal disorders as age-related macular degeneration, presumed ocular histoplasmosis syndrome, myopic
  • neovascularization has proven recalcitrant to treatment in most cases.
  • the only known treatment is laser
  • TGF- ⁇ The family of peptides known as TGF- ⁇ can both regulate cell growth and differentiation.
  • polypeptides can both stimulate and inhibit cell
  • TGFs of some type have been found in almost all tissues from all species of animals which have been examined so far.
  • TGF- ⁇ 2 is a well-characterized material. As noted above, it is a polypeptide having a molecular weight of about 25,000 D and is a dimer composed of two 12,500 D subunits which are linked by a disulfide bridge (Cheifetz et al., Cell (1987) 48 :408-415; Ikeda et al., Biochemistry (1987) 26:2406-2410). TGF- ⁇ 2 has been isolated from bovine demineralized bone (Seyedin et al., J. Biol. Chem. (1987) 262:1946-1949), porcine platelets (Cheifetz et al., Cell (1987) 48:409-415), human
  • TGF- ⁇ 1 and TGF- ⁇ 2 are found in many of the same cells. However, their mature sequences have only about 75-80% homology (Derynck et al., EMBO J. (1987) 7: 3737-3743). It has been established that the several species of TGF- ⁇ are coded for by different genes. (Madisen et al., DNA (1988) 7 : 1-8)
  • TGF- ⁇ 1 appears to seal the edge of surgical retinotomy in rabbits (See, Smiddy et al., "Transforming Growth Factor- ⁇ --A
  • TGF- ⁇ 2 has been found to stimulate collagen glycoprotein synthesis as well as cellular
  • TGF- ⁇ has been found to inhibit [ 3 H]thymidine incorporation by retinal pigment epithelial cells stimulated by platelet-derived growth factor, a-FGF, b-FGF and EGF. According to Leschey, this could be due to TGF- ⁇ being linked to a strong
  • TGF- ⁇ positively modulates the bioactivity of FGF in corneal endothelial cells.
  • This invention is a method of stabilizing or improving ocular vision related to macular degeneration of the mammalian eye, and in which the method comprises administering to the mammal an effective dose of TGF- ⁇ .
  • the type of TGF- ⁇ is TGF- ⁇ 2
  • an effective dose is at least 500 ng. More preferably, the effective dose is an amount of TGF- ⁇ in the range of 500-4000 ng. In another preferred embodiment, the effective dose is about 2700 ng.
  • TGF- ⁇ is administered by intraocular, subretinal, subscleral, suprachoroidal, intrascleral, intrachoroidal and
  • parenteral modes of administration Such administration may be carried out in association with vitrectomy, as detailed below, or without vitrectomy.
  • the method comprises an additional preceding step:
  • the method may include peeling an epiretinal membrane from the retina.
  • TGF- ⁇ 2 is administered in an effective amount as a concentrated solution by cannula to the portion of the retina requiring treatment.
  • the amount of TGF- ⁇ 2 is about 660, 1330 or 2700 ng.
  • the administration step is varied. In one embodiments it is divided between the subretinal space and above the damaged portion of the retina. In other modes, administration is suprachoroidal or intrascleral.
  • the retinal disorder to be treated is a macular hole formed as a result of age- related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • a method of maintaining or improving the ocular vision in macular degeneration calls for administering to the mammal an amount of TGF- ⁇ effective to stabilize or improve vision.
  • TGF- ⁇ administering to the mammal an amount of TGF- ⁇ effective to stabilize or improve vision.
  • the method includes treating retinal disorders, which are characterized by decreased connective or fibrous tissue, and comprises the steps of removing the vitreous humor from the eye;
  • TGF- ⁇ is administered in an amount sufficient to improve healing.
  • TGF- ⁇ is used to treat ocular disorders
  • TGF- ⁇ is administered by intraocular injection or by application to the cornea.
  • TGF- ⁇ can be applied to the cornea by means of eyedrops or a timed release capsule placed in the cul de sac.
  • the method provides for administration of TGF- ⁇ in an amount sufficient to promote healing and reduce symptoms associated with poor healing.
  • the amount of TGF- ⁇ administered is at least about 0.5 to 50 ⁇ g of TGF- ⁇ per treated eye.
  • a method for treating a mammal who has undergone or is about to undergo or is undergoing ophthalmic surgery to promote healing without excessive scarring comprising administering to said mammal TGF- ⁇ in an amount sufficient to promote healing without excessive scarring.
  • the ophthalmic surgery can be, but is not limited to, cataract extraction, with or without lens replacement; corneal transplants, surgery to treat viral infection or penetrating keratoplasty (PKP) ; glaucoma filtration surgery; and radial keratotomy and other types of surgery to correct refraction.
  • PGP penetrating keratoplasty
  • neovascularization comprising administering to a mammal an effective amount of TGF- ⁇ 2.
  • a method for treating a mammal for uveitis in which the method comprises injecting an effective amount of TGF- ⁇ intraocularly.
  • the Inventors propose that the administered TGF- ⁇ aids healing by modulating a fibrotic response in the ocular tissues.
  • application of an effective dose of TGF- ⁇ to the retina appears to provide positive neural regenerative effects as evidenced by macular flattening and by the fact that such TGF- ⁇ application significantly improves the eyesight of the individuals having the macular holes.
  • Figure 1 shows a graph of mean loss of visual acuity measured as mean line change in AMD patients treated with 665 ng TGF- ⁇ 2 (closed circles), 2600 ng TGF- ⁇ 2 (open circles), laser (closed squares) and
  • the method of this invention is suitable for the treatment of ophthalmic disorders, particularly retinal disorders involving macular degeneration,
  • neovascularization holes, separations, detachments, tears, and the like in the retina or between the retina and its underlying choroidal tissue, or involving
  • Opticular disorder refers to physiologic abnormalities of the eye. They may involve the retina, the vitreous humor, lens, cornea, sclera or other
  • Retinal wounds include, but are not limited to, tears and holes in the retina and detachment or separation from the underlying choroid. Retinal wounds appear after trauma, cystic degeneration, vitreoretinal traction, myopic degeneration, laser photocoagulation, lightning strike, pilocarpine administration and cataract extraction. To help the retina heal in a modulated process, TGF- ⁇ can be administered. "Macular degeneration" is commonly
  • TGF- ⁇ can help promote healing of the atrophied retinal pigment epithelium in a controlled fashion, which is designed to limit excessive fibroproliferation that may occur without such treatment.
  • Macular degeneration also presents in an exudative form in some patients. This disorder is associated with choroidal neovascularization.
  • Secondary cataracts are opacities in the ocular lens which interfere with vision. Secondary cataracts occur after x-ray exposure, in diabetes,
  • TGF- ⁇ can be used to promote healing of the lens after damage in a modulated fashion which is designed to limit
  • diseased corneal tissue includes damage to the cornea by a variety of causes including, but not limited to, damage due to trauma, surgery, radial keratotomy or excimer laser treatment, dry eyes (in which the conjunctiva on the inside of the eyelid may abrade the cornea), excessive light, allergens and infectious agents.
  • TGF- ⁇ can be used to promote gradual healing of diseased corneal tissues and avoid excessive scarring which can interfere with vision.
  • TGF- ⁇ can be used to control at least the ocular
  • first TGF- ⁇ can promote gradual healing without scarring of the tear gland and that second, TGF- ⁇ also promotes healing of corneal epithelial wounds which arise from the dry eye syndrome caused by lack of tear glands.
  • optical neovascularization is herein defined as the unwanted new growth of blood vessels into the ocular tissues. Unchecked, such growth can result in blindness.
  • the ocular tissues which can be invaded by neovascularization include the cornea, iris, retina, vitreous, and choroid. Many diseases and conditions cause or contribute to ocular neovascularization.
  • causes of corneal neovascularization include but are not limited to trauma, chemical burns or corneal transplantation.
  • neovascularization of the iris include but are not limited to diabetic retinopathy, vein occlusion, ocular tumor and retinal detachment.
  • causes of retinal and intravitreal neovascularization include but are not limited to diabetic retinopathy, vein occlusion, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia and trauma.
  • causes of choroidal neovascularization include but are not limited to retinal disorders of age-related macular degeneration, presumed ocular histoplasmosis syndrome, myopic
  • neovascularization is herein defined as treating ocular neovascularization which has already become detectable and may also include prophylactic treatment to prevent recurrence of neovascularization
  • Farm animals include, but are not limited to, cows, hogs, and sheep.
  • Sport animals include, but are not limited to, dogs and horses.
  • the category pets includes, but is not limited to, cats, dogs, and hamsters.
  • TGF- ⁇ Factor-beta
  • TGF- ⁇ has been found to stabilize neovascularized tissue and possibly reduce exudate. We have found that TGF- ⁇ is particularly effective in stabilizing or improving the vision of persons afflicted with age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the inventive methods involve the placement of at least an effective amount of a growth factor such as TGF- ⁇ , preferably TGF- ⁇ 2, on the ophthalmic abnormality.
  • TGF- ⁇ may be applied using known surgical techniques, such as those described in Example 1. In some cases it may be desirable that the TGF- ⁇ stay in place for a substantial period of time after application. For instance, a day is typically considered adequate for this purpose.
  • known surgical techniques such as those described in Example 1.
  • Hyaluronic acid is typically used in the eye for this purpose; however, as indicated by the data below, hyaluronic acid does not appear to increase treatment effectiveness.
  • AMD age-related macular degeneration
  • two treatment regimes have been found to be effective in at least improving or stabilizing the vision of AMD patients.
  • the first of these treatment regimes involves the local application of an effective amount of TGF- ⁇ to the macular region of the retina following vitrectomy.
  • the second regime a portion of the total dose is injected into the subretinal space and the remaining dose is applied above the retina in the area of the macula.
  • TGF- ⁇ it may be necessary for the patient to remain in a supine position for at least 24 hours, and to remain face down for as much time as possible for the following five days.
  • the above regimens are described in Example 2 below. They may be modified by application of TGF- ⁇ using suprachoroidal or intrascleral routes, according to methods known in the art.
  • a TGF- ⁇ dose of at least 500 ng and preferably at least 1000 ng is used for the treatment of AMD.
  • the dose will be in the range of 500 to 4000 ng. These doses appear to be the approximate dosage for improvement of vision (at least two lines on the Snellen Vision Chart). Although it is permissible to dissolve or suspend TGF- ⁇ 2 in suitable ophthalmic carriers such as normal saline solution, it is preferred that the material is in a relatively
  • TGF- ⁇ 2 TGF- ⁇ 2
  • the volumetric equivalent of a low dose is about 50 ⁇ l, while the high dose corresponds to about 200 ⁇ l, assuming a density of about 13.3 ng/ ⁇ l for TGF- ⁇ 2.
  • neovascularization and cystoid macula edema are described in Examples 3 and 8, respectively.
  • a concentrated solution of TGF- ⁇ or TGF- ⁇ 2 is placed on the macular hole itself and/or the edges of the macular hole.
  • Such treatments provide improvement of vision and healing by decreasing the thickness of the edge of the hole.
  • the edges of the hole appear to adhere to choroid or reconnect with the posterior hyaloid membrane.
  • use of the growth factor on other retinal abnormalities is effective.
  • the inventive treatment is applicable to retinal disorders, which include macular degeneration and macular holes, where it promotes healing and significantly improves vision.
  • the treatment also may be used on peripheral retinal holes and tears.
  • Suitable patients with an ophthalmic disorders amenable to TGF- ⁇ treatment can be identified by medical history, physical findings and laboratory tests.
  • the medical history reveals such facts as time of onset of symptoms such as red sclera, pain, photophobia, dry or gritty eyes, and vision changes, such as blurred vision not correctable with eyeglasses and double vision in an eye.
  • Patients with AMD sometimes complain of inability to engage in their usual activities, such as watching television or driving a car at night, and my progressively lose their abilities to discriminate colors and contrast.
  • Patients with ophthalmic disorders associated with impaired healing may have physical findings such as injected sclera, cotton-wool spots on the retina, a macular hole, bleeding behind the retina.
  • Indicative laboratory results include low levels of TGF- ⁇ in the serum or in eye tissues, such as the vitreous.
  • TGF- ⁇ may be administered by any of a variety of routes known in the art, including but not limited to, intraocular, subretinal, suprachoroidal, subscleral, intrascleral, intrachoroidal, and subconjunctival
  • injection depending on the nature and location of the pathology being treated. Also contemplated in the present invention are administration by intravenous injection, subcutaneous injection, or oral
  • a concentrated solution of TGF- ⁇ is injected into the eye and placed immediately over the lesion, for example, on the retina.
  • TGF- ⁇ may be administered in any combination
  • compositions including, but not limited to, solutions, suspensions, and timed-release preparations, such as microcapsular particles and
  • preferred dose is greater than about 1000 ng (measured at an absorbance of 210 or 280 nm wavelength). More
  • the dose is about 1100 ng.
  • the preferred dose is about 2500 ng.
  • TGF- ⁇ 2 may be administered in a slow-release device embedded in the tissue stroma or in a compartment adjacent to the affected tissue.
  • TGF- ⁇ in a pellet of ethylene vinyl copolymer 2 mm in diameter could be surgically implanted in the vitreous cavity or suprachoroidal space to release TGF- ⁇ over time. This modality is believed to be
  • problems include those who have undergone or about to undergo surgery.
  • Examples of such surgery include, but are not limited to, Cataract extraction, with or without lens replacement;
  • TGF- ⁇ promotes prompt, gradual healing without excessive fibrous tissue formation.
  • growth factors which have both wound healing and neurotrophic effects can be applied in certain of these inventive treatments. These factors include, but are not limited to, acidic and basic
  • fibroblast growth factor insulin, insulin-like growth factor, platelet-derived growth factor, nerve growth factor, epidermal growth factor, transforming growth factor ⁇ , colony-stimulating factor, keratinocyte growth factor, and tissue plasminogen activator, connective tissue growth factor (CTGF), leukocyte-derived growth factor (LDGF), and keratinocyte growth factor (KGF).
  • CTGF connective tissue growth factor
  • LDGF leukocyte-derived growth factor
  • KGF keratinocyte growth factor
  • Macular holes are classified as Stage 4 when a posterior vitreous detachment is present. Treatment was scheduled within 2 weeks of the baseline examination. Under the criteria, patients were excluded if they had greater than 2+ nuclear sclerotic or posterior
  • Doses of 70 ng, 330 ng, and 1330 ng of TGF- ⁇ 2 were administered.
  • the 70 ng dose was chosen to provide a negative control for the higher doses.
  • the 330 ng dose was believed to be at the low end of the effective range, and the 1330 ng dose was believed to be well within the effeetive range.
  • Eyes were randomly chosen for the indicated doses of intravitreal TGF- ⁇ 2. In addition, some eyes separately received 100 ⁇ l of intravitreal hyaluronic acid at the time of instillation of TGF- ⁇ 2 in an attempt to delay clearance of TGF- ⁇ 2 from the area of the macular hole. Although effective in conjunction with TGF- ⁇ 2, co- administration of hyaluronic acid appeared to lessen benefits from TGF- ⁇ 2.
  • an epiretinal membrane was found; however, no definite edges of this membrane could be found. Where encountered, the epiretinal membrane was peeled from the surface of the retina and removed from the eye. In other cases, no definite epiretinal membrane could be found; however, there appeared to be some gelatinous condensation on the inner surface of the retina surrounding the macular hole for approximately 200-400 ⁇ , with a firm adhesion along the margin of the macular hole. This was carefully dissected where
  • TGF- ⁇ 2 was supplied by Celtrix
  • TGF- ⁇ 2 was highly purified (greater than 95% purity), and derived from bovine bone. The reconstituted formulation
  • TGF- ⁇ 2 contained either 70, 330, or 1330 ng/0.1 cc of TGF- ⁇ 2 after dilution with a diluent solution. Eyes were randomly assigned a dose of TGF- ⁇ 2. About 0.1 cc of TGF- ⁇ 2 solution was gently infused into the macular hole. In about 50% of eyes, a comparable volume of hyaluronic acid was also introduced in order to determine if this might maintain the presence of the TGF- ⁇ 2 solution, thereby improving efficacy.
  • the patient was instructed to lie in a supine position for the first 24 hours following surgery; thereafter, the patient was instructed to remain in a face-down position as much as possible over the ensuing two weeks.
  • Treatment effects were assessed using logistic regression.
  • the dependent variable was improvement in visual acuity of two or more lines on the Snellen Chart, and the independent variables were TGF- ⁇ 2 dose and hyaluronic acid use.
  • the posterior hyaloid surface was completely separated from the retina in all eyes with Stage 2 and Stage 3 macular holes. However, in all eyes with Stage 2 macular holes, this separation of the posterior hyaloid surface from the retina extended marginal dehiscence and formed an
  • the macular region could be adequately examined using a biomicroscope with a contact lens or a 78 diopter lens.
  • Microscopic retinal detachment and retinal thickening surrounding the macular hole could be readily assessed at this time.
  • flattening of the detachment and thinning of the adjacent retina to a normal-appearing thickness occurred in 12/12 eyes treated with 330 ng of TGF- ⁇ 2 without hyaluronic acid and 11/11 eyes treated with 1330 ng of TGF- ⁇ 2 without hyaluronic acid.
  • only 6/11 eyes treated with 70 ng TGF- ⁇ 2 without hyaluronic acid had the edges of the macular hole flatten after 4-6 weeks.
  • the addition of hyaluronic acid to the TGF- ⁇ 2 gave unexpected results.
  • Table 1 As the data in Table 1
  • hyaluronic acid significantly suppressed the rate of flattening of the retina around the macular hole.
  • Visual acuity did not improve in eyes with no improvement in retinal flattening.
  • Final visual acuity improved two lines or more in lo/ll eyes treated with 1330 ng TGF- ⁇ 2 without hyaluronic acid, 4/12 eyes treated with 330 ng TGF- ⁇ 2 without hyaluronic acid, and 5/11 eyes treated with 70 ng TGF- ⁇ 2 without hyaluronic acid.
  • hyperfluorescent window defect corresponding to the base of the macular hole in most eyes. Postoperatively, angiography showed a decrease of the central
  • Wound healing is important in the treatment of numerous retinal disorders.
  • This example describes the first use of TGF- ⁇ in the treatment of a retinal disorder with improvement of vision.
  • the posterior hyaloid was separated from the retina in eyes having Stage 2 or Stage 3 macular holes.
  • a gelatinous, friable material accumulated along the margins of the holes, but only limited attempts were made to remove the material for fear of damaging the adjacent neurosensory tissue.
  • this method limits manipulation of the retina and induces chorioretinal adhesion using TGF- ⁇ .
  • the edges of the macular holes were flattened in 23/23 (100%) eyes treated with 330 or 1330 ng TGF- ⁇ 2 without hyaluronic acid.
  • a fine bead of fibrous tissue could be observed along the margin of the macular hole after it flattened. This fibrous tissue was accompanied with good visual recovery (vision improvement of two or more
  • TGF- ⁇ 2 might cause excessive fibrosis which can increase macular contraction and result in proliferative vitreoretinopathy (PVR) .
  • PVR proliferative vitreoretinopathy
  • TGF- ⁇ 2 also enhanced recovery of the photoreceptor outer segment function, possibly by neural regeneration or stimulation of accessory tissues which in turn help stabilize and align neural retinal cells.
  • ASD Age-related Macular Degeneration
  • bovine TGF- ⁇ 2 bovine TGF- ⁇ 2
  • the therapeutic efficacy and safety of locally administered bovine TGF- ⁇ 2 was compared to a placebo or no treatment in patients with exudative age-related macular degeneration and visual acuity of 20/160 or better.
  • the primary efficacy variable was change in visual acuity from baseline in the respective treatment groups.
  • the secondary efficacy variable was stabilization (within 2 lines on ETDRS) or improvement ( ⁇ 2 lines on ETDRS) of visual acuity compared to baseline measurements. Further efficacy measurements were
  • At least one high risk characteristic a. subretinal serous exudate
  • retinopathy macular hole, retinal detachment, uncontrolled glaucoma, or advanced visual field loss
  • angiogram were centered on field II of the eye. Stereo angiographic views were taken during the transit phase, and at 30, 40, 60, 90 seconds, 2, 3, 5, and 10 minutes centered on field II. At 10 minutes there were also a stereo view of field I of the eye. Additional views of the opposite eye and of other fields were obtained at the discretion of the treating ophthalmologist. In addition, the ICG angiogram were taken using a similar protocol, but ICG views were taken at 40 minutes as well. All study photographs and angiograms were labeled with the patient's code at the clinic. Photographs and angiograms were read by an observer masked with respect to patient information and randomization code.
  • a 3 mm infusion cannula was to be placed 4 mm posterior to the limbus, and held in place with a pre-placed 4-0 white silk mattress suture. In each case, the tip of the cannula was seen within the vitreous cavity prior to the onset of infusion.
  • Two additional sclerotomies were made at 10 o'clock and 2 o'clock meridians, 4 mm posterior to the limbus.
  • a light pipe and vitreous cutter were then introduced. At this point, a core vitrectomy was performed in the involved eye. After completing the core vitrectomy, the vitreous cutter was removed and replaced with a cannula having a flexible silicone tip.
  • the cannula was then connected to the aspiration system of the vitrectomy machine and aspiration set at 150 mm Hg.
  • the infusion bottle was positioned approximately 50 cm above the level of the patient's head.
  • the tip of the cannula was positioned approximately 1 mm above the surface of the retina just below the superotemporal arcade. Full aspiration was applied, and the cannula gently elevated. After the posterior hyaloid surface was elevated in the area just inferior to the superotemporal arcade, the cannula was used to extend this posterior hyaloid detachment as far as possible out to the equator. In some cases,
  • the instruments were then removed from the eye, and replaced with scleral plugs.
  • the peripheral retina were examined with indirect ophthalmoscopy and scleral depression in order to ensure that no retinal tears occurred.
  • the scleral plugs were then removed, and the light pipe and flexible-tipped cannula were reintroduced.
  • a fluid-air exchange was performed aspirating all fluid over the optic disc.
  • the instruments were then removed from the eye and replaced with scleral plugs. Fifteen minutes were allowed for peripheral fluid to drain posteriorly.
  • the scleral plugs were once again removed, and the light pipe and flexible-tipped cannula were reintroduced. Additional fluid that migrated posteriorly was aspirated.
  • the viscodissection cannula and tubing (Visitec, Inc.) was then connected to a 1 cc syringe containing freshly diluted bTGF- ⁇ 2, or placebo.
  • the tip of the cannula was positioned just over the area of neovascularization and 200 ⁇ l containing 1330 ng/100 ⁇ l bTGF- ⁇ 2 solution or placebo solution was gently infused.
  • the instruments were then removed from the eye, and the two superior sclerotomies were closed with 7-0 vicryl.
  • the infusion cannula was removed, and the sclerotomy closed with 7-0 vicryl.
  • the intraocular pressure was checked, and the intravitreal bubble was adjusted to achieve normal pressure.
  • the conjunctiva was closed with interrupted 6-0 collagen.
  • the patient received acetazolamide, 500 mg intravenously (IV) and continued on acetazolamide 250 mg by mouth or IV every six hours, for the next 24 hours.
  • the patient was instructed to lie in a supine position for the first 24 hours following surgery; thereafter to remain in a facedown position as much as possible over the ensuing five days.
  • the patients in Group I received 50 ⁇ l (665 ng) of bTGF- ⁇ 2 subretinally in the area of the neovascular net, with another 150 ⁇ l (1995 ng) of bTGF- ⁇ 2 applied directly onto the fovea at its interface with the vitreous cavity.
  • Subjects assigned to Group II were treated in the same manner as those in Group I except that they received a placebo (vehicle) solution identical to the drug product but without bTGF- ⁇ 2, while those in Group III were untreated.
  • the total dose administered was 200 ⁇ l (2660 ng) of highly purified bTGF- ⁇ 2 extracted from bovine bone and supplied as a concentrated acidic solution (Vial 1, MS 2004) which was mixed with diluent containing human serum albumin (Vial 2, MS 2005) prior to subretinal or intravitreal injection.
  • the final concentration of bTGF- ⁇ 2 following mixing with the diluent was 2660 ng per 200 ⁇ l volume of solution (Group I), or 200 ⁇ l of placebo (Group II).
  • the placebo preparation was an acidic solution without bTGF- ⁇ 2 (Vial 1, MS 2009) which was mixed with diluent (Vial 2, MS 2005) prior to subretinal or intravitreal injection.
  • Final concentrations of diluent materials in the injected solution are as
  • sub-RPE subretinal pigment epithelial
  • subretinal neovascularization associated with AMD using TGF- ⁇ 2 is described.
  • the study involves 50 patients who satisfy the study criteria for sub-RPE or sub-retinal
  • Another group of patients is injected with 50 ⁇ l in the subretinal space and 150 ⁇ l within the vitreous cavity above the area of the sub-RPE or sub-retinal neovascularization. After twenty patients are treated, the data are evaluated to determine whether any safety modifications to the protocol are appropriate.
  • Baseline studies include visual acuity measurement (standardized Snellen and ETDRS eye charts) and biomicroscopy as described in Example 2, as well as both fluorescein and ICG angiography to document the presence of the sub-RPE or sub-retinal
  • Safety and efficacy assessments include visual acuity measurements, biomicroscopic visualization of the fovea, and fluorescein and ICG angiography.
  • the posterior hyaloid surface is elevated in the area just inferior to the superotemporal arcade, the posterior hyaloid is detached as far as possible out to the equator. In some cases, additional manipulation is needed at the disc in order to complete the detachment of the posterior hyaloid surface.
  • a total pars plana vitrectomy is performed by removing the vitreous as far out to the periphery as possible.
  • the retina is examined to assure that no retinal tears have occurred.
  • TGF- ⁇ 2 Freshly thawed TGF- ⁇ 2 is suspended in buffer containing 2% human serum albumin for a concentration of 1330 ng/100 ⁇ l TGF- ⁇ 2 solution. TGF- ⁇ 2 solution (either 50 ⁇ l or 200 ⁇ l) is applied to the area of
  • neovascularization In patients receiving subretinal TGF- ⁇ 2, a bent, tapered 33-gauge cannula is used to enter the subretinal space at a site at least one disc diameter from the center of the fovea. Gentle injection of 50 ⁇ l containing 1330 ng/ 100 ⁇ l TGF- ⁇ 2 is performed. The additional 150 ⁇ l of TGF- ⁇ 2 is injected within the vitreous cavity just over the area of neovascularization. The conjunctival flaps and sclerotomies are closed. The intraocular pressure is checked and the intravitreal bubble adjusted to achieve normal pressure.
  • the patient receives acetazolamide, 500 mg IV, and is continued on acetazolamide, 250 mg PO or IV every six hours, for the next 24 hours.
  • the patient is instructed to lie in a supine position for the first 24 hours following surgery; thereafter, the patient is instructed to remain in a face-down position as much as possible over the next five days.
  • Patients are examined at one day, two weeks, four to six weeks, and at three, six and twelve months after surgery.
  • the patients are examined for best corrected visual acuity for both distance and near vision, refraction, intraocular pressure, size of
  • neovascular net presence of epiretinal membrane, presence of hyperfluorescence on fluorescein angiography, lens status, and results of ICG angiography.
  • the inventive treatment is also considered to be beneficial in other ocular disorders such as retinal edema, retinal vascular disorders, wound healing
  • TGF- ⁇ Effects of TGF- ⁇ on Neovascularization
  • various doses of TGF- ⁇ were implanted into the clear cornea of rabbits in the triple pocket corneal assay, as detailed in Example 5, and the neovascular response was measured over time.
  • TGF- ⁇ 1 and TGF- ⁇ 2 and vehicle controls were placed in 2.5 isogel agarose (FMC Corp., Rockland, ME).
  • Porcine platelet-derived TGF- ⁇ 1 and TGF- ⁇ 2 lyophilized without bovine serum albumin (BSA) were obtained from Drs. Anita Robert and Michael Sporn (NIH, Bethesda, MD).
  • BSA bovine serum albumin
  • Porcine platelet-derived TGF- ⁇ 1 lyophilized with BSA also was obtained from R&D systems, Inc. (Minneapolis, MN). The duplication of sources was used to help control for the method of procurement, handling and shipment
  • TGF- ⁇ 1 and TGF- ⁇ 2 were solubilized in 4 mM HCl.
  • the agarose was heated to 60° C, added to the solubilized peptides and then allowed to gel at room temperature.
  • the gelled agarose was then divided into 2 X 1.5 X 1 mm implants for implantation into the rabbit cornea.
  • TGF- ⁇ 1 When TGF- ⁇ 1 was implanted into a nonvascular rabbit cornea, there was a dose-dependent stimulation of blood vessel growth in 82% of corneas implanted with 1, 5, 25 and 100 ng. The majority of corneas implanted with 1 ng of TGF- ⁇ showed no neovascular ingrowth. The remaining 1 -ng-treated corneas had sparse, short blood vessels. As the dose increase from 5 to 100 ng, the neovascularization became more dense, the blood vessels were longer, and the corneas became more edematous. At two days post-implantation, an intrastromal neovascular response was evident and became more prominent at days 4 and 6.
  • administering TGF- ⁇ 1 or TGF- ⁇ 2 without any preexisting neovascularization may cause
  • the triple pocket corneal assay includes first administration of an agent to produce neovascularization in one compartment, followed by implantation of TGF- ⁇ 1, TGF- ⁇ 2 or a control on both sides of the
  • Neovascularization was induced by implanting in the cornea a pellet containing either PGE1 (Upjohn Co., Kalamazoc, MI) or TGF-alpha (Chemicon International, Inc., El Segundo, CA).
  • PGE1 Upjohn Co., Kalamazoc, MI
  • TGF-alpha Chemicon International, Inc., El Segundo, CA.
  • the PGE1 was solubilized in absolute alcohol and then added to a casting solution of 10% ethylene vinyl coacetate polymer in methylene
  • TGF- ⁇ was solubilized in 1 mM HCl and then added to agarose and divided into implants.
  • TGF- ⁇ 1 , TGF- ⁇ 2 or control pellets were implanted next to actively growing blood vessels and on either side of the primary implant to test for the effect on the angiogenic activity.
  • TGF- ⁇ 1 and TGF- ⁇ 2 were used at doses of 1, 3, 5, 10, 25, 100 and 200 ng (6 corneas for each dose, except for 8 for the 100 ng dose).
  • TGF- ⁇ 1 was implanted at the 50 ng dose.
  • implants contained an equivalent volume of vehicle (4 mM HCl) or 100 ng of platelet-derived growth factor (PDGF from R&D Systems, Inc.) solubilized in 4 mM HCl.
  • vehicle 4 mM HCl
  • PDGF platelet-derived growth factor
  • the pockets for the secondary implants were formed by one-half-thickness incisions which were 1.5 mm long and perpendicular to and 1.5 mm from the limbus and 3-4 mm from the primary implant. Two pockets were formed on either side of the primary implant by gently inserting a cyclodialysis spatula into the incised edge of the cornea and advancing the spatula in a plane parallel to the curvature of the cornea to within 1.0 mm of the primary implant such that the pockets lay 1.5 mm from and parallel to the limbus.
  • Blood vessel lengths were measured adjacent to the TGF- ⁇ -containing implant (E) and the control implant (C) 2 mm from the center of the primary implant ( Figure 1). The relative lengths of the blood vessels in these areas were then expressed as a ratio: E/C (the length of the blood vessels in the area of the TGF- ⁇ implant divided by the length of the blood vessels in the area of the control implant). Percent stimulation or inhibition was calculated by subtracting 1.0 from E/C and
  • Serial 5-micron frozen sections were taken from a cornea implanted with 100 ng of TGF- ⁇ in a triple pocket assay, stained with hematoxylin and examined by light microscopy.
  • TGF- ⁇ enhanced neovascularization in 89% of corneas at doses of 1, 3 and 5 ng. At 1 ng,
  • neovascularization was enhanced by 47%; at 3 ng, 118%; and at 5 ng, 67% relative to control on day 4.
  • TGF- ⁇ 1 stimulated neovascularization much more than TGF- ⁇ 2 at the 1 ng dose (about 55% and 40%, respectively) and 3 ng dose (180% and 56%, respectively).
  • the 50 ng dose of TGF- ⁇ 1 inhibited neovascularization by 59% on day 2, 49% on day 4 and 29% on day 6.
  • the dose of 10 ng appeared to be a
  • both TGF- ⁇ 1 and TGF- ⁇ 2 can inhibit neovascularization caused by PGE1 or TGF- ⁇ .
  • TGF- ⁇ 2 is superior in having less
  • the inventors propose that the different effects above and below 10 ng may be due to the interplay of TGF- ⁇ on multiple functions, including causing chemotaxis in blood monocytes at about 0.1 to 1.0 pg/ml, inducing gene expression for interleukin-1 (at least IL-1 ⁇ -specific mRNA has been observed in cultured monocytes) at 1.0 to 25 ng/ml, and inhibiting vascular endothelial cell proliferation at 0.1 to 10.0 ng/ml.
  • interleukin-1 at least IL-1 ⁇ -specific mRNA has been observed in cultured monocytes
  • vascular endothelial cell proliferation at 0.1 to 10.0 ng/ml.
  • TGF- ⁇ In another rabbit triple pocket corneal assay study, 100 ng of PDGF and 100 ng of TGF- ⁇ 1 and TGF- ⁇ 2 (four corneas for each peptide) were the secondary implants after the initial 1.5 ug PGE1 neovascular stimulus. TGF- ⁇ inhibited neovascularization relative to PDGF in 100% of corneas. TGF- ⁇ 1 and TGF- ⁇ 2 showed comparable degrees of inhibition.
  • the average blood vessel length in the area of the TGF- ⁇ implant was 19%, 40% and 36% of the average blood vessel length in the area of the PDGF implant on days 2, 4 and 6, respectively (combined data for ⁇ 1 and ⁇ 2).
  • TGF- ⁇ 300 ng TGF- ⁇ neovascular stimulus.
  • TGF- ⁇ also inhibited neovascularization stimulated by TGF- ⁇ at a dose of 300 ng.
  • TGF- ⁇ inhibited neovascularization in 100% of corneas.
  • TGF- ⁇ 1 and TGF- ⁇ 2 had comparable degrees of inhibition.
  • the combined average blood vessel length in the area of the TGF- ⁇ implant was 47%, 51% and 47% of the blood vessel lengths around the control implant on days 2, 4 and 6, respectively.
  • TGF- ⁇ 1 and TGF- ⁇ 2 were compared with PDGF, which served as a negative protein control.
  • results of the experiment indicates that the anti-neovascularization effects of TGF- ⁇ 1 and TGF- ⁇ 2 are specific to these proteins and are not due to
  • the effect of TGF- ⁇ 2 on healing after corneal surgery for correction of myopia and hyperopia is determined by measuring the magnitude of effect that TGF- ⁇ 2 has on altering the corneal topography in three different types of corneal incisions.
  • Radial non-penetrating radial incisions are made.
  • One group of animals receives two radial incisions and the other group receives four radial incisions using a knife with micrometer adjusted to cut up to 90% of the central corneal thickness. Both eyes are operated. With the aid of an operating microscope, the 3.5 mm central optical zone centered over the pupil is demarcated with a marker.
  • Radial incisions start at the central optical zone and extend peripherally to within about 2-3 mm of the limbus.
  • Circular incisions are made with corneal trephines of different diameters and penetrate about 90% of the corneal depth. At the end of surgery, 2.0 ⁇ g or 5.0 ⁇ g TGF- ⁇ 2 or control solution is applied to each eye.
  • TGF- ⁇ 2 is applied to one incision (after which a cup is placed over the incision to keep the medication from dispersing) and the other incision is not treated. This helps assess the effect of TGF- ⁇ 2 on the change in topography.
  • antibiotic ointment is topically applied to the eyes.
  • the eyes are observed under the slit lamp and corneal topographic measurements are made, both before and at regular intervals after surgery.
  • the slit lamp is used to evaluate corneal vascularization, epithelial healing, depth of incisions (to assess healing) and the amount of scar tissue formed. Corneal topographic measurements will help assess how symmetrically and quickly the eyes stabilize.
  • the cats are euthanized, and sections of the eyes are mounted on slide, stained and compared.
  • the eyes receiving TGF- ⁇ 2 treatment have rapid, strong healing and early
  • CME Cystoid Macula Edema
  • bovine bone-derived TGF- ⁇ 2 (bTGF- ⁇ 2) was applied onto the macula of patients with cystoid macula edema (CME) following vitrectomy with the intent to reduce the magnitude of retinal edema and to improve visual acuity.
  • bTGF- ⁇ 2 bovine bone-derived TGF- ⁇ 2
  • Parameters to be assessed include visual acuity (EDTRS eye chart), macular status (biomicroscopy and fluorescein angiography), adverse events (lens status, intraocular pressure, and retinal detachment), and concomitant medications.
  • ocular disease e.g. macular
  • Baseline studies include a complete medical and ophthalmologic history and an ophthalmic examination with visual acuity measurements. Best corrected visual acuity is measured using the ETDRS eye chart.
  • CME is confirmed by slit lamp biomicroscopy using a fundus contact lens or 78 diopter lens. Color fundus photographs (30o) are taken of the disc and macula (photographic fields I and II). Fluorescein angiography is used to confirm the diagnosis of CME using
  • photographs are labeled with the patient's study code and the date of the photograph, and subsequently graded by a certified grader who is masked with regard to either the patient's study code or the time the photographs were taken relative to treatment.
  • Treatment is scheduled within one week (seven days) of the date on which the baseline tests are
  • a vitreous cutter and fiberoptic light pipe are then introduced into the vitreous cavity.
  • the anterior and central vitreous are removed. Any visible vitreous adhesions to the anterior segment, iris, or lens capsule are severed.
  • the posterior vitreous is then removed with the vitreous cutter. Each eye is examined for a
  • posterior vitreous detachment using a flexible silicone tip cannula attached to the suction line of the vitreous cutter console.
  • a suction of 150 mm Hg is applied approximately 2-3 mm superior to the fovea, about 0.2 to 0.5 mm anterior to the retina, to determine if there is residual posterior cortical vitreous with an attached posterior hyaloid. If the posterior hyaloid is still attached, the silicone tip cannula is used to create a posterior vitreous detachment.
  • the posterior hyaloid is removed with the vitreous cutter to at least the equator.
  • the silicone tip cannula is used to verify that the posterior hyaloid has been completely removed posterior to the equator.
  • the vitreous cutter and fiberoptic light pipe is removed from the eye, and the sclerotomies closed with scleral plugs.
  • the peripheral retina is examined with indirect ophthalmoscopy and scleral depression to look for any peripheral retinal breaks. Peripheral breaks, if present, are treated with cryopexy.
  • the scleral plugs are then removed, and the light pipe and silicone tip cannula are reintroduced into the vitreous cavity. A fluid-air exchange is performed, aspirating the
  • Visitec The viscodissection cannula and tubing (Visitec) are then connected to a 1 cc syringe containing TGF- ⁇ 2 freshly diluted in neutral buffer supplemented with 2% human serum albumin.
  • viscodissection cannula is positioned directly over the fovea, taking care not to touch the fovea with the cannula.
  • a 0.1 ml aliquot (1330 ng) of TGF- ⁇ 2 is
  • the instruments are removed from the eye, and the two superior sclerotomies closed with 7-0 vicryl suture.
  • the infusion cannula is removed, and the remaining sclerotomy closed with 7-0 vicryl suture.
  • the intraocular pressure is normalized with sterile air to achieve an intraocular pressure of about 10 mm Hg.
  • the conjunctiva is then closed with
  • Intraocular pressure if abnormally high, IOP is treated first with topical aqueous suppressants such as ⁇ -blockers or ⁇ -blockers; oral carbonic anhydrase inhibitors are only used if topical therapy has been deemed inadequate to control the intraocular pressure
  • topical aqueous suppressants such as ⁇ -blockers or ⁇ -blockers
  • oral carbonic anhydrase inhibitors are only used if topical therapy has been deemed inadequate to control the intraocular pressure
  • the size of the gas bubble remaining the anterior segment, including the cornea, anterior chamber, and lens, with slit lamp biomicroscopy; adverse events; and concomitant medication.
  • subcapsular cataract formation both of which are graded on a scale of 0-4; the severity of cystoid macular edema is assessed by slit lamp biomicroscopy on a 0-4 scale; the severity of cystoid macular edema from fluorescein angiographic photographs by a certified grader who is masked with regard to patient identity and visitation date; the presence or absence of an epiretinal membrane; adverse events; and changes in concomitant medications.
  • the invention has been described by example and by words. It is the Inventors' intent that the examples not be used to limit the scope of the invention and further that equivalents to the claims expressed below be considered within the scope of the invention.

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Abstract

L'invention concerne un procédé de traitement de la dégénérescence maculaire et, en particulier, de la dégénérescence maculaire due au vieillissement. Ce procédé consiste à appliquer une dose efficace du facteur de croissance transformant β (TGF-β) à la zone de la rétine nécessitant le traitement. Selon un premier schéma de traitement, on applique le TGF-β localement au-dessus de la zone de la macule après avoir effectué la vitrectomie de l'oeil. Selon un deuxième schéma de traitement, on injecte une partie de la dose totale de TGF-β dans l'espace sous-rétinal et on applique localement le reste de la dose au-dessus de la zone de la macule. On réalise également ce deuxième schéma de traitement pendant ou après la vitrectomie de l'oeil. On peut également administrer le TGF-β par d'autres voies, notamment par les voies intrasclérale ou suprachoroïdienne.
PCT/US1995/011316 1994-09-28 1995-09-08 PROCEDE DE TRAITEMENT DE LA DEGENERESCENCE MACULAIRE AU MOYEN DE TGF-$g(b) WO1996009838A1 (fr)

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EP0831868A1 (fr) * 1995-06-07 1998-04-01 The Schepens Eye Research Institute, Inc. Therapie oculaire contre le syndrome de sjogren faisant appel a une application topique d'androgenes ou du facteur de croissance transformant beta
EP0831868A4 (fr) * 1995-06-07 2000-07-12 Schepens Eye Res Inst Therapie oculaire contre le syndrome de sjogren faisant appel a une application topique d'androgenes ou du facteur de croissance transformant beta
WO2000007565A2 (fr) * 1998-08-03 2000-02-17 Insite Vision, Incorporated Procedes d'administration ophtalmique
WO2000007565A3 (fr) * 1998-08-03 2000-05-11 Insite Vision Inc Procedes d'administration ophtalmique
US6309374B1 (en) 1998-08-03 2001-10-30 Insite Vision Incorporated Injection apparatus and method of using same
US6378526B1 (en) 1998-08-03 2002-04-30 Insite Vision, Incorporated Methods of ophthalmic administration
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AU761830B2 (en) * 1998-08-03 2003-06-12 Insite Vision Incorporated Methods of ophthalmic administration
EP1252895A4 (fr) * 2000-01-31 2003-04-16 Santen Pharmaceutical Co Ltd Remedes pour troubles ophtalmiques
EP1252895A1 (fr) * 2000-01-31 2002-10-30 Santen Pharmaceutical Co., Ltd. Remedes pour troubles ophtalmiques
US11944703B2 (en) 2006-02-22 2024-04-02 Clearside Biomedical, Inc. Ocular injector and methods for accessing suprachoroidal space of the eye
US11752101B2 (en) 2006-02-22 2023-09-12 Clearside Biomedical, Inc. Ocular injector and methods for accessing suprachoroidal space of the eye
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