CRISPR Editing May Lead To Genetic Treatment of Retinitis Pigmentosa

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Benjamin Bakondi, Ph.D. Postdoctoral Scientist, Eye Program Board of Governors Regenerative Medicine Institute Cedars-Sinai Medical Center; Dept. of Biomedical Sciences Los Angeles, CA 90048

Dr. Benjamin Bakondi Interview with:
Benjamin Bakondi, Ph.D. Postdoctoral Scientist
Laboratory of: Shaomei Wang, M.D., Ph.D.
Institute Director: Clive N. Svendsen, Ph.D.
Board of Governors Regenerative Medicine Institute
Cedars-Sinai Medical Center;
Dept. of Biomedical Sciences
Los Angeles, CA 90048

Medical Research: What is the background for this study? What are the main findings?

Dr. Bakondi: Retinitis Pigmentosa (RP) is an inherited disease that causes progressive retinal degeneration and continual vision loss. Over 130 mutations have been identified in over 60 genes that cause RP. Gene replacement therapy is being evaluated for the recessive form of RP, in which both inherited alleles are dysfunctional. Retinitis Pigmentosa arising from dominant mutations however, would not benefit from such a strategy, and alternative options have not demonstrated clear efficacy.

The idea for a therapeutic based on our approach is to use CRISPR/Cas9 to ablate the mutant copy of an allele and leave the wild-type copy unaffected. Barring haploinsufficiency, the wild-type allele should restore function and prevent retinal degeneration at levels commensurate with Cas9 cleavage efficiency. Our experimental findings provide proof-of-principle that a single DNA nucleotide difference in the genomic sequence between mutant and wild-type genes is enough to distinguish the mutant transcript for Cas9 cleavage with high fidelity. Eliminating production of the mutant rhodopsin protein prevented retinal degeneration and preserved vision. While Cas9/gRNA delivery improvement is underway, it should be noted that translational applicability of this approach is restricted to dominant mutations, not all of which may be targetable for ablation therapy.

Medical Research: What should clinicians and patients take away from your report?

Dr. Bakondi For physician scientists: It is useful to have DNA mutations of adRP patients sequenced and available to investigators in a searchable online database format, in accordance with HIPAA regulations. This information will help laboratory researchers determine if mutations are targetable using gene editing tools available currently, or by those under development. These data should coincide with the availability of patient samples (fibroblast or other culture-expandable cells) for in vitro testing. The ability to obtain patient cells is vital in order for researchers to evaluate the utility of their experimental designs when based on the patients’ unique mutation. Data gathered from such experiments may be provided to granting and regulatory agencies as proof-of-principle on which translational and potentially clinical studies may be based.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Bakondi Provide access to patient DNA sequence data for other investigators.


Benjamin Bakondi, Wenjian Lv, Bin Lu, Melissa K. Jones, Yuchun Tsai, Kevin J. Kim, Rachelle Levy, Aslam A. Akhtar, Joshua J. Breunig, Clive N. Svendsen, Shaomei Wang. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa. Molecular Therapy, 2015; DOI:10.1038/mt.2015.220

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Benjamin Bakondi, PhD (2016). CRISPR Editing May Lead To Genetic Treatment of Retinitis Pigmentosa 

Last Updated on January 20, 2016 by Marie Benz MD FAAD