DEFINING PATIENT COHORTS FOR GUIDING CLINICAL TRIALS AND TREATMENT IN LAFORA DISEASE: A MODEL FOR THE RARE DISEASE COMMUNITY
Year of Publication
Doctor of Philosophy (PhD)
Molecular and Cellular Biochemistry
Dr. Matthew S. Gentry
In the US, approximately 8000 rare diseases have been identified. Combined, rare diseases impact more than 30 million people in the U.S. alone, with 75% of those being children. However, research, funding, and therapeutic development for the rare disease community remains challenging because of the incredible diversity – not only between diseases, but often even within a single disease.
LD is an ultra-rare childhood dementia and epilepsy caused by mutations in one of two driver genes: EPM2A, which encodes for the glycogen phosphatase laforin, and EPM2B/NHLRC1, which encodes the E3 ubiquitin ligase malin. Children with LD develop seemingly normal until their pre-teen years when they experience increasingly severe seizures coupled with neurodegeneration. While all patients follow the same trajectory, there is substantial variation in the rate of their decline. This variability presents a challenge for therapeutic development and structuring clinical trials.
To that end, this work presents a method for rapid characterization of novel EPM2A mutations. Additionally, this work devises a strategy for interrogating differences and similarities between the two driver genes of LD. This information is then used to assess the impact and viability of an antisense oligonucleotide (ASO) therapy to halt disease progression in LD. Finally, these lessons are extrapolated to build a genotype-phenotype correlation for Glut1 Deficiency Syndrome, another rare metabolic disease, showing the adaptability of these methods for the broader rare disease community.
Digital Object Identifier (DOI)
This study was supported by National Institute of Neurological Disorders and Stroke (R01 N070899, P01 NS097197) from 2017-2020, National Science Foundation (MCB-1817414) in 2018, and National Institute of Neurological Disorders and Stroke (R35 NS116824) from 2021-2022.
Donohue, Katherine Janae, "DEFINING PATIENT COHORTS FOR GUIDING CLINICAL TRIALS AND TREATMENT IN LAFORA DISEASE: A MODEL FOR THE RARE DISEASE COMMUNITY" (2022). Theses and Dissertations--Molecular and Cellular Biochemistry. 61.
Available for download on Saturday, December 30, 2023