The term “macular degeneration-related disorder” refers to any of a number of conditions in which the retinal maculal degenerates or becomes dysfunctional as a consequence of decreased growth of cells of the macular, increased death or rearrangement of the cells of the macula, loss of normal biological function, or a combination of these events. Macular Degeneration-related Disordersinclude age-related macular disorder (AMD), North Carolina macular dystrophy, Sorsby’s fundus dystrophy, Stargardt’s disease, pattern dysterophy, Best disease, dorminant drusen and radial drusen (“malattia leventinese”).

Age-Related Macular Degeneration (AMD):

AMD is the major cause of irreversible blindness worldwide. AMD is characterized by a progressive loss of vision in the critical central portion of the visual field.  This visual loss is caused by degeneration of the macula, a small circular region of the neural retina that is responsible for one’s ability to appreciate detail and read fine print. Individuals with AMD find images in the important central porition of the visual field greatly blurred or non-existent.

AMD is the elading cause of visual loss in people over 55. Two major clinical phenotypes of AMD are recognized –a nonexudative (dry) type and an exudative (wt) type. (Bora, J. Immunology, 174, 2005, pp. 491-497)

Types of AMD: 

1. Wet AMD: The  more severe form of AMD is typically diagnosed in the late stages of the disease and is associated with the ingrowth of blood vessels into the retina. Wet AMD is characterized by growth of abnormal blood vessels behind the retina under the macula. This “neovascular” form of AMD is responsible for about 90% of the severe visual loss (20/200 or worse). Choroidal neovascularization (CNV) which refers to abnormal or excessive formation of new blood vessels in the chorid layer of the eye. These new blood vessels are fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal place at the back of the eye, causing loss of central vision.

2. Dry AMD: An earlier atrophic, stage of the disease is manifested by abnormal deposition of cellular and extracellular materials in association with Bruch’s membrane and the nearby vascular bed (the choriocapillaris), especially in the macular region. Some of these deposits are termed drusen, based on the German word for nodule. Drusen are concentrated between the retinal pigmented epithelium (RPE) basal lamina and the choriocapillaris. A number of studies have concluded that the presence of macular drusen is a strong risk factor for the development of both atrophic and neovascular AMD (Hageman, Molecular Vision, 1999, 5:28). Dry AMD is characterized by slow breakdown of light sensitive cells in the macula, gradually blurring central vision in the affeced eye. Over time, less of the macula funcitons and central vision is gradually lost.

Etiology:

–Presence of complement moleules:

Inhibitors of complement, such as factor H and CD59, have ben shown to impact the development of choroidal neovascularization in response to laser induced damage of Bruch’s membrane (US8324182).

Various complement components have been found to be associated with AMD Zeng “Lack of association of CFD polymorphisms with advanced age-related macular degeneration” Molecular Vision 2010)

–Drusen and Vitronectin

Vitronectin (also termed “complement S-protein” is a complement inhibitor which binds to C5b-7 and C9. (Milis, Clin Exp Immunol. 92: 114-9, 1993)

Drusen and Vitronectin has been identified as a principal molecular constituent of drusen and other abnormal deposits associated with AMD. On the basis of this identification, WO 95/17673 describes an invention for diagnostics for early AMD based on the presence of abnormal concentrations of vitronectin as well as agents which dissolve or remove drusen and blcok the deposition of vitronectin which comprise drusen.

Treatment: 

1. Phtodynamic therapy: Wet AMD is treated with laser surgery, photodynamic therapy and injections into the eye. These treatments slow progression but do not cure.There is no known form of treatment for advanced stage dry AMD and vision loss is inevitable (US8324182).

2. Anti-angiogenic agents:

–Anti-VEGF: Current treatment for AMD and other types of choroidal neovascularization involve administration of anti-angiogenic agents. Current evidence supports the use of ranibizumab (Roche) which binds to certain subtypes of VEGF as first-line therapy (harding, Eye, 2010, 24 497-505). (see also Cimerli (ranibizumab-eqrn) by Coherus Biosciences). 

—

3. Anti-oxidants: Some reports suggest that orally administered antioxidants (e.g., vitamins E and C, selenium, beta-caroteine) may reduce its incidence and/or severity. Based on this information, AMD patients are advised by some opthalmologists to limit their exposure to intense sunlight, and/or to consider supplementing their diets with multivitamins and trace minerals. A specific high dose formulation of antioxidants and zinc has been shown to prevent intermediate stage AMD from progression to advanced AMD.

4. Complement Inhibition:

Bora discloses that for AMD of the exudative (wet) type the complement system such as the membrane attack complex (MAC) is involved in the etiology of the disease. Bora ruptured Bruch’s membrane as a mouse model for choroidal neovascularization (CNV) of the wet type AMD and found that anti-murine C6 Abs inhibited MAC formationand also resulted in the inhibition of CNV.

Hageman teaches methods for treating ocular diseases such as macular degeneration by administering an effective amount of a therapeutic agent which modulates a complement pathway assocaited moelecule (US Patent Applicaiton 15/897,609, published as US 2018/0335436) such as antibodies which modulate the level of at least one complement pathway assocaited molecule (US 2003/0207309A1).

Fung (US 12/092346) also teaches methods for the treatment of ocular related diseases such as AMD, diabetic retinopathy, ocular angiogenesis by adminsitering complement inhibitors such as those to the alternative complement pathwaqy such as Factor D. See also therapeutic application of antibodies 

6. Difficulties in treatment

Kovesdi (US2007/0098692) states that disorders associated with both neovascular and atrophic components, such as age-related macular degeneration and diabetic retinopathy, are particularly difficult to treat due to the emergence of a wide variety of complications (§3). Giordano (US 2007/0077233) also states that “age-related macular degeneration is clinically difficult to treat (§51).

Zeng “Lack of association of CFD polymorphisms with advanced age-related macular degeneration” Molecular Vision 2010) discloses that AMg is a complex disease cuased by the combination of genetic prediposition and environmental factors and that none of 6 single nucleotide polymorphisms (SNps) of complement factor D were found to be significanly assocaited with advanced AMD.