Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy

• Published in: Molecular therapy Vol. 31; no. 7; pp. 2014 - 2027
• Main Authors: Hanna, Kelly, Nieves, Julio, Dowd, Christine, Bender, Kristina Oresic, Sharma, Pallavi, Singh, Baljit, Renz, Mark, Ver Hoeve, James N., Cepeda, Diana, Gelfman, Claire M., Riley, Brigit E., Grishanin, Ruslan N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-07-2023; American Society of Gene & Cell Therapy
• Subjects: AAV; animal models; Animals; blue cone monochromatism; cone photoreceptors; fovea; gene therapy; Genetic Therapy - methods; Humans; inherited retinal disorder; intravitreal; non-human primate; OPN1LW; Opsins - genetics; Original; Primates - genetics; Primates - metabolism; Retinal Cone Photoreceptor Cells - metabolism; Rod Opsins - genetics; Rod Opsins - metabolism; animal models; non-human primate; cone photoreceptors; blue cone monochromatism; OPN1LW; AAV; inherited retinal disorder; fovea; gene therapy; intravitreal
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.03.011

Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 1010 vg/eye resulted in transduction of 18%–85% of foveal cones. A Good Laboratory Practice (GLP) toxicology study established that IVT administration of ADVM-062 was well tolerated at doses that could potentially achieve clinically meaningful effect, thus supporting the potential of ADVM-062 as a one-time IVT gene therapy for BCM.
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Hanna and colleagues have developed ADVM-062, an intravitreal AAV.7m8 ocular gene therapy for blue cone monochromacy designed to deliver human L-opsin to cone photoreceptors. The study demonstrates meaningful foveal cone transduction in NHPs at well-tolerated doses, thus supporting potential clinical development of ADVM-062 as a gene therapy for BCM patients.