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other·ophthalmology, retina, neuro-ophthalmology, preclinical research, neurology·PMC10616160

Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators

Scientific Reports · 15 authors, 6 centres

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TL;DR

In two mouse models of familial dysautonomia, intravitreal AAV2-mediated ELP1 gene replacement and oral administration of the splicing modulator PTC680 both significantly reduced retinal ganglion cell death, providing proof-of-concept pre-clinical data for potential FD treatments.

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This study tested two therapeutic strategies in complementary mouse models of familial dysautonomia (FD): AAV2-mediated ELP1 gene replacement via intravitreal injection and oral delivery of the splicing modulator PTC680. PTC680 (1.2 mg/kg/day) in a hybrid TgFD9 model increased RGC numbers by up to 57% across three treatment start ages, including when initiated at P90. These results provide foundational pre-clinical evidence for both gene replacement and splicing modulation as potential therapeutic approaches for FD-related retinal degeneration.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10616160

Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators

Scientific Reports

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ABSTRACT

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 ( ELP1 ) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.

CITATION EXPORT

Anastasia Schultz, Shun-Yun Cheng, Emily Kirchner et al.. Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators. Scientific Reports. (2023). https://doi.org/10.1038/s41598-023-45376-w

AUTHORS

15 · 6 CENTRES

Anastasia Schultz, Shun-Yun Cheng, Emily Kirchner, Stephanann Costello, Heini Miettinen, Marta Chaverra, Colin King, Lynn George, Xin Zhao, Jana Narasimhan, Marla Weetall, Susan Slaugenhaupt, Elisabetta Morini, Claudio Punzo, Frances Lefcort

1https://ror.org/02w0trx84grid.41891.350000 0001 2156 6108Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT USA
2https://ror.org/0464eyp60grid.168645.80000 0001 0742 0364Department of Ophthalmology, Neurobiology and Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA USA
3https://ror.org/002pd6e78grid.32224.350000 0004 0386 9924Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA USA
4https://ror.org/002pd6e78grid.32224.350000 0004 0386 9924Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA USA
5https://ror.org/01tj58m37grid.260198.40000 0000 8816 0949Department of Biological and Physical Science, Montana State University Billings, Billings, MT USA
6https://ror.org/03jz67a83grid.417479.80000 0004 0465 0940PTC Therapeutics, Inc., South Plainfield, NJ 07080 USA