Base and Prime Editing in the Retina—From Preclinical Research toward Human Clinical Trials

Abstract

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases that are one of the leading causes of vision loss in young and aged individuals. IRDs are mainly caused by a loss of the post-mitotic photoreceptor neurons of the retina, or by the degeneration of the retinal pigment epithelium. Unfortunately, once these cells are damaged, it is irreversible and leads to permanent vision impairment. Thought to be previously incurable, gene therapy has been rapidly evolving to be a potential treatment to prevent further degeneration of the retina and preserve visual function. The development of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) base and prime editors have increased the capabilities of the genome editing toolbox in recent years. Both base and prime editors evade the creation of double-stranded breaks in deoxyribonucleic acid (DNA) and the requirement of donor template of DNA for repair, which make them advantageous methods in developing clinical therapies. In addition, establishing a permanent edit within the genome could be better suited for patients with progressive degeneration. In this review, we will summarize published uses of successful base and prime editing in treating IRDs.

Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models

“…This powerful mechanism can be harnessed to knock-out-specific genes or facilitate the insertion of a donor sequence at the DSB site utilising endogenous DNA repair pathways [ 148 , 149 ]. Recent advancements in this technology have given rise to novel editing systems like base and prime editors [ 150 , 151 ]. The field of gene editing is rapidly evolving, expanding the repertoire of available tools and enabling a wider range of edits with increasing precision.…”

Adeno-Associated Virus (AAV) - Based Gene Therapies for Retinal Diseases: Where are We?

“…Thus, reconstitution occurs at the protein level. 60 , 61 Two recent studies showed interesting results in rd12 mice, an LCA model involving the RPE65 gene with nonsense mutation c.130C>T, p.(R44X). 28 , 62 Both teams performed dual-AAV delivery of split-ABEs to correct point mutation and reached 3% and 6% A>G editing at the DNA level in RPE cells, leading to retinal function improvements.…”

In vivo rescue of genetic dilated cardiomyopathy by systemic delivery of nexilin

“…Due to the lack of pathogenicity, low immunogenicity, and durable expression of the therapeutic components even in non-dividing cells such as cardiomyocytes, leading AAV-mediated gene replacement therapy is a promising method in treating cardiac disorders [ 22 – 25 ]. Currently, several AAV serotypes have been identified and applied in both scientific research and clinical treatment [ 26 – 30 ]. Among them, AAV serotype 9 (AAV9) is considered to be the most effective mammalian cardiomyocyte transducer from systemic injections [ 31 , 32 ].…”