%0 PDF %T Development of Novel Therapeutics for the Treatment of Age-related Macular Degeneration. %A Leaderer, Derek. %D 2017-04-14T13:36:54.204Z %8 2017-04-14 %R http://localhost/files/m326mc85j %X Abstract: Age-related macular degeneration (AMD) is one of the most common causes of central vision loss among the elderly, yet treatment options remain extremely limited. The 'wet' form of AMD, characterized by choroidal neovascularization (CNV), is currently treated with repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, intravitreal injections are associated with complications and long-term inhibition of VEGF leads to macular atrophy. Thus, there is currently an unmet need for the development of therapies for CNV that target molecules other than VEGF. We describe nucleolin as a novel target for the 'wet' form of AMD. This study demonstrated that when injected intravitreally, AS1411, a previously described G-quartet oligonucleotide that has been shown to bind nucleolin and induce cellular senescence, co-localized with the site of laser-induced CNV and inhibited CNV formation in vivo. Finally, topical application of AS1411 led to a reduction in CNV, making AS1411 an intriguing potential therapeutic that targets a non-VEGF pathway and whose topical application would negate any injection associated complications. Another major limitation is that there currently is no treatment available for 'dry' AMD, which accounts for 90% of all cases. To address this we developed novel soluble chimera inhibitors of human complement, a portion of the immune system whose over-activation is strongly linked to the development and progression of AMD. The chimera complement inhibitors SACT (CD46-CD55-CD59) and DTAC (CD55-CD59) exhibited properties similar to CD46, CD55 and CD59 or CD55 and CD59 respectively in vitro and prevented human membrane attack complex (MAC) deposition on murine retinal pigment epithelium (RPE) in an ex vivo setting. Additionally, AAV-mediated expression of SACT or DTAC protected murine liver vasculature from human MAC deposition in an in vivo setting. Overall, SACT and DTAC merit further study as potential therapies for AMD and other complement mediated disorders when delivered via a gene therapy approach. An additional issue in treating AMD is the inability of potential therapeutically beneficial macromolecules to penetrate the retina and readily cross the plasma membrane of retinal cells. Utilizing AS1411 to target the nucleolin pathway and bypass endosomal entrapment, we developed a platform technology for delivering exogenous proteins to the retina and cornea. Overall, this body of work furthers the field of ocular medicine by addressing each of the aforementioned limitations in our current treatment of age-related macular degeneration.; Thesis (Ph.D.)--Tufts University, 2017.; Submitted to the Dept. of Genetics.; Advisor: Rajendra Kumar-Singh.; Committee: Janis Lem, Thomas Linsenmayer, Gordon Huggins, and Edward Feener.; Keyword: Genetics. %[ 2022-10-11 %9 Text %~ Tufts Digital Library %W Institution