Translatability barriers between preclinical and clinical trials of AAV gene therapy in inherited retinal diseases

Alizeh Shamshad; Chaerim Kang; Laura A Jenny; Elijah M Persad-Paisley; Stephen H Tsang

doi:10.1016/j.visres.2023.108258

Translatability barriers between preclinical and clinical trials of AAV gene therapy in inherited retinal diseases

Vision Res. 2023 Sep:210:108258. doi: 10.1016/j.visres.2023.108258. Epub 2023 May 25.

Authors

Alizeh Shamshad¹, Chaerim Kang¹, Laura A Jenny², Elijah M Persad-Paisley¹, Stephen H Tsang³

Affiliations

¹ Warren Alpert Medical School of Brown University, USA.
² Edward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY, USA; Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY, USA.
³ Edward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY, USA; Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; Department of Biomedical Engineering, Columbia University, New York, NY, USA; Columbia Stem Cell Initiative, Columbia University, New York, NY, USA; Insitute of Human Nutrition, Columbia University, New York, NY, USA.

PMID: 37244011
PMCID: PMC10526971 (available on 2024-09-01)
DOI: 10.1016/j.visres.2023.108258

Abstract

Inherited retinal diseases (IRDs) are progressive degenerative diseases which cause gradual vision loss or complete blindness. As over 270 gene mutations have been identified in the underlying pathology of IRDs, gene therapy as a treatment modality has been an increasingly active realm of investigation. Currently, the most common vehicle of ocular gene delivery is the adeno-associated virus (AAV) vector. This is injected into the immune-privileged subretinal space to mediate transgene expression in retinal cells. Although numerous animal models of IRDs have demonstrated successful outcomes following AAV-mediated gene delivery, many of these studies fail to translate into successful outcomes in clinical trials. The purpose of this review is to A) comparatively assess preclinical and clinical IRD trials in which the success of AAV-mediated therapy failed to translate between animal and human participants B) discuss factors which may complicate the translatability of gene therapy in animals to results in humans.

Keywords: AAV; Gene therapy; Inherited retinal disease; Viral vector.

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dependovirus* / genetics
Genetic Therapy / methods
Humans
Models, Animal
Retina / metabolism
Retinal Diseases* / genetics
Retinal Diseases* / metabolism
Retinal Diseases* / therapy

Abstract

Publication types

MeSH terms

Grants and funding