Institution: Clemson University, South Carolina, U.S.
Primary Investigator: Trudy Mackay, PhD, Director, Clemson Center for Human Genetics and Self Family Endowed Chair of Human Genetics
Duration: 24 months
Start Date: January 2022
Type of Sanfilippo studied: A
Types of Sanfilippo that could benefit: A; with possible translation to B, C, and D
Research Stage: Basic
Cure Sanfilippo Foundation has awarded funding to Trudy Mackay, PhD, of Clemson University to comprehensively characterize knock-out and patient-specific mutation drosophila (fly) models of Sanfilippo Syndrome (MPS IIIA) and to test for gene modifications that alter the severity of the disease.
Drosophila (fruit flies) are an excellent genetic model system since they mimic 75% of the human genome, are cost efficient to grow and maintain, and due to naturally-short lifespan are able to provide more rapid answers to research question than some larger animal models.
Among the mucopolysaccharidosis (MPS) disorders there is an incomplete understanding of how impaired glycosaminoglycan (GAG) degradation and secondarily-altered biologic pathways impact patients’ neurological function. This incomplete knowledge creates a barrier for identifying new therapeutic strategies.
Dr. Mackay plans to overcome this barrier by using an unbiased “systems biology approach” to uncover genetic modifiers of disease.
Using the gold standard Drosophila Genetic Reference Panel resource, originally developed by Dr. Mackay and her collaborator Dr. Arnholt, the team will cross 200 drosophila lines with fly lines carrying various Sanfilippo mutations. Creation of these fly lines, previously funded by Cure Sanfilippo Foundation, includes mutations associated with severe and attenuated human phenotypes. Genome-wide differences in gene expression evaluation by RNA sequencing will identify which “non-Sanfilippo” genes most significantly affect disease severity. The team, which also includes lysosomal disease experts Drs. Richard Steet and Heather Flanagan-Steet, will examine the biochemical, pathological, and behavioral impacts of these genetic alterations.
Modifiers of disease symptoms and/or lifespan may reveal new cellular pathways that impact disease within the nervous system, and new therapeutic targets or biomarkers for Sanfilippo syndrome. If the genes identified are able to be targeted by FDA-approved drugs, an expedited pathway toward human clinical trials may be possible.
“Our team is excited about the potential for this project to lead to a greater understanding of why MPS IIIA patient variants have such large effects on nervous system function, and the prospect of identifying loci that ameliorate these symptoms and lead to therapeutic treatments,” said Dr. Mackay.
Learnings from this study of drosophila models of Sanfilippo will inform further applications for other Sanfilippo subtypes.
This page’s content has been reviewed by Dr. Cara O’Neill, FAAP and Trudy Mackay, PhD.