Gene Therapy of ABCA4-Associated Diseases

Abstract

The ATP-binding cassette (ABC) transporter gene, ABCA4 (ABCR), was characterized in 1997 as the causal gene for autosomal recessive Stargardt disease (STGD1). Shortly thereafter several other phenotypes were associated with mutations in ABCA4, which now have collectively emerged as the most frequent cause of retinal degeneration phenotypes of Mendelian inheritance. ABCA4 functions as an important transporter (or "flippase") of vitamin A derivatives in the visual cycle. Several ways to alleviate the effects of the defective ABCA4 protein, which cause accumulation of 11-cis and all-trans-retinal in photoreceptors and lipofuscin in the retinal pigment epithelium, have been proposed. Although ABCA4 has proven to be a difficult research target, substantial progress through genetic, functional, and translational studies has allowed major advances in therapeutic applications for ABCA4-associated pathology, which should be available to patients in the (near) future. Here, we summarize the status of the gene therapy-based treatment options of ABCA4-associated diseases.

MonoallelicABCA4Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study

“…The finding that carriers of monoallelic ABCA4 mutations were phenotypically normal in our setting has implications for future therapeutic approaches. Gene replacement therapy is currently pursued, 41 but challenges include the large size of the ABCA4 coding region, the relatively inefficient viral transduction of photoreceptors, and a possibly low diseasespecific efficiency of gene delivery. 42 However, the lack of haploinsufficiency in the pathogenesis of ABCA4-mediated retinal and macular degenerations shown here suggests that gene therapy may be effective despite these challenges.…”

The Primary Cilium as a Therapeutic Target in Ocular Diseases

“…However, the traditional AAV vehicle has limited carrying capacity, and DNA fragments of about 4.3 kb cannot be genetically edited using traditional techniques. The double-AAV strategy appears to be able to overcome this limitation; for example, ATP binding cassette subfamily A member 4 (ABCA4) or RP1 genes of more than 5 kb can be transmitted with two different AAV vectors ( Auricchio et al., 2015 ; Nanda et al., 2019 ).…”

Viral Delivery Systems for CRISPR

“…However, it is difficult to control the dose of the added alleles. More importantly, many disorders are caused by genes with sizes that exceed the packaging capacities of viral vectors, making it impossible to add full-length alleles as a method to correct the underlying disorder [8,9]. Researchers have explored multiple viral vectors and delivery methods in order to expand the carrying capacities and the spectrum of disorders that can be treated.…”