Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration.

Ruslan Grishanin,Claire Gelfman,Brian Vuillemenot,Wenzheng Hu,Matthew Lawrence,Mehdi Gasmi,Judith Greengard,Mark Blumenkrantz,Szilárd Kiss,Annahita Keravala,Pallavi Sharma

doi:10.1016/j.ymthe.2018.11.003

Ruslan Grishanin, Claire Gelfman + Show 9 more

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https://doi.org/10.1016/j.ymthe.2018.11.003

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Inhibition of vascular endothelial growth factor, a key contributor to the choroidal neovascularization associated with wet age-related macular degeneration, is the mode of action of several approved therapies, including aflibercept, which requires frequent intravitreal injections to provide clinical benefit. Lack of compliance with the dosing schedule may result in recurrence of active wet macular degeneration, leading to irreversible vision impairment. Gene therapy providing sustained anti-vascular endothelial growth factor levels in the retina following a single injection could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, is optimized for intravitreal delivery and strong protein expression. Here, we report the long-term expression and efficacy of ADVM-022-derived aflibercept in a laser-induced choroidal neovascularization model in non-human primates. Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels. In addition, ADVM-022 administration 13 months before lasering prevented the occurrence of clinically relevant choroidal neovascularization lesions, similar to animals that received a bolus of intravitreal aflibercept (standard of care) at the time of lesioning. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for wet macular degeneration and may ultimately improve patients’ visual outcomes.

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Age-related macular degeneration (AMD) is the most common cause of vision impairment in individuals 50 years of age and older
The tropism of the AAVserotype 2 (AAV2).7m8 capsid and distribution of GFP-transduced cells in African green monkeys, observed by fundus fluorescence imaging by cSLO, corroborated the data described in Dalkara et al.,[18] with strong transduction in fovea and peripheral retina, areas known to have a thin inner limiting membrane (Figure S1)
Compliance with the treatment regimen for these therapies can constitute a considerable burden to patients[7] and a survey of 90 retinal specialists with large clinical practices determined that reduced dosing frequency is the greatest unmet need in wet” or exudative form of AMD (wAMD) therapy.[33]

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Introduction

Age-related macular degeneration (AMD) is the most common cause of vision impairment in individuals 50 years of age and older. Degeneration of the macula, which plays a critical role in detailed central vision, leads to blurred or distorted areas within the central visual field.[1,2] Approximately 10% to 20% of patients with AMD develop abnormal blood vessel formation in the choroid layer area under the macula. This choroidal neovascularization (CNV) results in the “wet” or exudative form of AMD (wAMD), which is characterized by leakage of blood and fluid from the abnormal new vessels into the retina. Accumulation of fluid within the retina leads to photoreceptor degeneration, secondary scarring,[2] and vision loss.

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