Small molecule

Susan Slaugenhaupt, PhD, Scientific Director of the Mass General Research Institute; Professor, Department of Neurology at Mass General and Harvard Medical School; Investigator; Center for Genomic Medicine and Elisabetta Morini, PhD, Assistant Professor of Neurology, Mass General and Harvard Medical School.

FD is caused by a mutation in the ELP1 gene that disrupts mRNA splicing, leading to a reduced amount of ELP1 protein. ELP1 protein is essential for the proper development and maintenance of neurons in the sensory and autonomic nervous system and in the retina. The small molecule called kinetin corrects the splicing defect and increases the production of full-length, functional ELP1 protein.  Increasing ELP1 protein has been shown to rescue the disease in animal models. Kinetin has served as the starting point for medicinal chemistry and optimization, leading to small molecules with significantly improved efficacy and potency.

 

Gene therapy

Frances Lefcort, PhD, Professor, Cell Biology and Neuroscience, Montana State University (retired).

Anil Chekuri, PhD, Investigator, Massachusetts Eye and Ear; Instructor in Ophthalmology Harvard Medical School.

Gene replacement therapy is an effective and FDA-approved strategy for delivering a healthy copy of a gene that, when mutated, causes disease. We have developed an AAV2 vector that drives the expression of the wild type human ELP1 gene in human cell lines and in FD mouse models. Gene therapy can be delivered systemically or to a particular target, such as the retina. As people with FD enter their teens, they develop a progressive optic neuropathy that leads to vision loss, severely compromising quality of life. We have demonstrated that intravitreal administration of our ELP1 gene replacement vector into our FD mouse model can increase levels of ELP1 protein in the retina and significantly reduce the death of retinal neurons (Schultz et al., 2023). The goal now is to conduct the necessary testing required to establish safety and effectiveness in higher mammals.

 

ASO (antisense oligonucleotide)

Horacio Kaufmann, M.D, Director, Dysautonomia Center
Adrian Krainer, PhD, St. Giles Foundation Professor, Cancer Center Program Co-Leader, Cold Spring Harbor Labs.

n-Lorem Foundation

FD results from a point mutation in a RNA splicing site which interferes with normal production of ELP1 protein. Antisense oligonucleotides are strands of nucleic acids that are designed to bind to specific regions of the genes to thereby rectify the disrupted splicing of a gene. Dr. Krainer and collaborators developed an ASO that increases the production of ELP1 protein in human cells and in FD mouse models. Working with the n-Lorem Foundation, it is now being tested in a small clinical trial.


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