subretinal-injection-gene-therapy-vectors-stem-cells-perinatal-mouse

Subretinal Injection of Gene Therapy Vectors and Stem Cells in the Perinatal Mouse Eye

The loss of sight affects approximately 3.4 million people in the United States and is expected to increase in the upcoming years.1 Recently, gene therapy ...

murine-orchiectomy-and-ovariectomy-to-reduce-sex-hormone-production

Murine Orchiectomy and Ovariectomy to Reduce Sex Hormone Production

Sex hormone signaling plays a critical role in multiple organ systems as well as in the progression of various diseases, including neurodegenerative ...

Columbia University 

UT Southwestern Medical Center

The metabolic environment is important for neuronal cells, such as photoreceptors. When photoreceptors undergo degeneration, as occurs during retinitis pigmentosa (RP), patients have progressive loss of vision that proceeds to full blindness. Currently, there are no available treatments for the majority of RP diseases. We performed metabolic profiling of the neural retina in a preclinical model of RP and found that TCA cycle intermediates were reduced during disease. We then determined that (a) promoting citrate production within the TCA cycle in retinal neurons during disease progression protected the photoreceptors from cell death and prolonged visual function, (b) supplementation with single metabolites within the TCA cycle provided this therapeutic effect in vivo over time, and (c) this therapeutic effect was not specific to a particular genetic mutation but had broad applicability for patients with RP and other retinal degenerative diseases. Overall, targeting TCA cycle activity in the neural retina promoted photoreceptor survival and visual function during neurodegenerative disease.

Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa.

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.

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

Batten disease is characterized by cognitive and motor impairment, retinal degeneration, and seizures leading to premature death. Recent studies have shown efficacy for a gene therapy approach for CLN7 Batten disease. This gene therapy approach is promising to treat cognitive and motor impairment, but is not likely to delay vision loss. Additionally, the natural progression of retinal degeneration in CLN7 Batten disease patients is not well-known.

ArticleTotal : 2	Year
Publication title	2012
Publication title	2023

Article	Year
Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa. JCI insight\| PubMed ID: 34292885	2021
Base and Prime Editing in the Retina-From Preclinical Research toward Human Clinical Trials. International journal of molecular sciences\| PubMed ID: 36293232	2022
Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics. EBioMedicine\| PubMed ID: 36374771	2022
Human retina-in-a-dish: Unlocking the potential to study mechanisms of inherited retinal disease. Molecular therapy. Methods & clinical development\| PubMed ID: 37693947	2023

Katherine J. Wert

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