Molecular therapy. Nucleic acidsMar 5, 2024

Gene replacement therapy using AAV works in retinal models of AIPL1-related early vision loss

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 9, 2026

Abstract

Biallelic variations in the AIPL1 gene cause Leber congenital amaurosis subtype 4 (LCA4), an early-onset retinal dystrophy with severe sight impairment.

Gene replacement therapy using adeno-associated virus may effectively rescue molecular features associated with LCA4 in human retinal organoid models.
Treatment led to the restoration of retinal phosphodiesterase 6 levels and a reduction in elevated cyclic guanosine monophosphate (cGMP) levels.
Transcriptomic analysis indicated changes in gene expression linked to the treatment and viral infection.
Current evidence suggests that AIPL1 gene therapy could be a promising intervention for LCA4.

Simplified

Biallelic variations in the() gene cause Leber congenital amaurosis subtype 4 (LCA4), an autosomal recessive early-onset severe retinal dystrophy that leads to the rapid degeneration of retinal photoreceptors and the severe impairment of sight within the first few years of life. Currently, there is no treatment or cure for-associated LCA4. In this study, we investigated the potential of adeno-associated virus-mediatedgene replacement therapy in two previously validated human retinal organoid (RO) models of LCA4. We report here that photoreceptor-specificgene replacement therapy, currently being tested in a first-in-human application, effectively rescued molecular features of-associated LCA4 in these models. Notably, the loss of retinal phosphodiesterase 6 was rescued and elevated cyclic guanosine monophosphate (cGMP) levels were reduced following treatment. Transcriptomic analysis of untreated and AAV-transduced ROs revealed transcriptomic changes in response to elevated cGMP levels and viral infection, respectively. Overall, this study supports AIPL1 gene therapy as a promising therapeutic intervention for LCA4. aryl hydrocarbon receptor interacting protein-like 1AIPL1AIPL1AIPL1AIPL1AIPL1

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Gene replacement therapy using AAV works in retinal models of AIPL1-related early vision loss

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