Analysis of Aflibercept Expression in NHPs following Intravitreal Administration of ADVM-022, a Potential Gene Therapy for nAMD
| Autor: | Julio Nieves, Romeo J. Rosario, Szilard Kiss, Judith Greengard, Mehdi Gasmi, Aivan Nguyen, Ruslan Grishanin, Claire M. Gelfman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 Genetic enhancement Pharmacology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Therapeutic index Genetics Medicine lcsh:QH573-671 Molecular Biology Aflibercept Retina business.industry lcsh:Cytology Retinal Intravitreal administration Vascular endothelial growth factor Vascular endothelial growth factor A lcsh:Genetics 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Molecular Medicine business medicine.drug |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 18, Iss, Pp 345-353 (2020) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | Several standard-of-care therapies for the treatment of retinal disease, including aflibercept, inhibit vascular endothelial growth factor (VEGFA). The main shortcoming of these therapies is potential undertreatment due to a lack of compliance resulting from the need for repeated injections. Gene therapy may provide sustained levels of anti-VEGFA proteins in the retina following a single injection. In this nonhuman primate study, we explored whether ADVM-022, a recombinant adeno-associated virus (AAV) vector designed to express aflibercept, could induce anti-VEGFA protein levels comparable with those observed following a single-bolus intravitreal (IVT) injection of the standard-of-care aflibercept recombinant protein. The results demonstrated that intraocular levels of aflibercept measured at 56 days after a single IVT injection of ADVM-022 were equivalent to those in the aflibercept recombinant protein-injected animals measured 21–32 days post-administration. ADVM-022-injected animals exhibited signs of an initial self-limiting inflammatory response, but overall all doses were well tolerated. ADVM-022 administration did not result in systemic exposure to aflibercept at any dose evaluated. These results demonstrated that a single IVT injection of ADVM-022 resulted in safe and efficacious aflibercept levels in the therapeutic range, suggesting the potential of a gene therapy approach for long-term treatment of retinal disease with anti-VEGF therapy. Graphical Abstract Current treatments of nAMD require frequent intravitreal injections of VEGF inhibitors. ADVM-022 is a one-time intravitreal gene therapy designed to express aflibercept. Kiss et al. demonstrated a range of ADVM-022 doses in non-human primates that resulted in safe ocular expression of aflibercept in the therapeutic range, without systemic exposure. |
| Databáze: | OpenAIRE |
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