Development of Novel Therapeutics for the Treatment of Age-related Macular Degeneration.
Leaderer, Derek.
2017
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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 ... read moreare 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.read less - ID:
- m326mc85j
- Component ID:
- tufts:20412
- To Cite:
- TARC Citation Guide EndNote
