Biochemistry In Epilepsy Research - Lafora Disease - Matthew Gentry, University of Florida Health, USA
Podcast:
Biochemist Matt Gentry shares with us his extensive research into the ultra-rare epilepsy Lafora Disease, his motivation from working with families, the brilliant work of the Lafora Disease charity Chelsea’s Hope, and support from both the NIH and the Chan Zuckerberg Initiative.
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Meet Matt
Metabolisms go further than doughnuts - Brain metabolism
Identifying Lafora Disease
Lafora at the protein level & global team
Research & breakthroughs
Children progress fast but potential treatments have been stopped
Different landscape for treatments
Insights into more common disease(s) found through Lafora research
Motivation - natural curiosity, NIH, and families
Global family with Lafora Disease
What patients and families go through
Survivors guilt & support for families & research through Chelsea's Hope
IDC-10 Code to track patients with Lafora Disease
Scientists working with families
Chan Zuckerberg Initiative
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Matthew Gentry is Director of the NIH-funded Lafora Epilepsy Cure Initiative (LECI) and Chair of Biochemistry & Molecular Biology at University of Florida. The LECI is a consortium of Lafora disease (LD) researchers from around the world funded by a NIH P01 (PI: Gentry) to define the basic mechanisms of LD and translate the findings into pre-clinical therapies. LD is a glycogen storage disease, progressive myoclonic epilepsy, and childhood dementia. He has been working on LD for 17 years to define the disease-causing mechanisms of this fatal autosomal recessive disease and to develop therapies. This work has yielded three therapeutic platforms: traditional small molecule, anti-sense oligonucleotide, and an antibody-enzyme fusion. Each drug targets glycogen and either down-regulates glycogen metabolism or degrades aberrant glycogen-link accumulations. He is also PI of a non-overlapping NINDS R35 on brain metabolism and has been continuously funded by NIH since 2007. Collectively, the Sun and Gentry labs established a pipeline to perform traditional and spatial metabolomics on samples from control and diseased mice that yield foundational insights into both normal and diseased metabolic pathways. Collaborating with the Sun laboratory at UF, the Gentry laboratory studies: Alzheimer’s disease, Lafora disease, Glut1 Deficiency Syndrome, Pompe disease, Cori disease, traumatic brain injury, spinal cord injury, lung cancer, and Ewing sarcoma while collaborating with numerous other labs on exciting projects.
LD is caused by mutations in either the gene encoding for laforin or the gene encoding for malin that when mutated results in pathogenic polyglucosan bodies (PGBs). He discovered the activity of malin as an E3 ubiquitin ligase and laforin as a glycogen phosphatase, characterized their biochemical properties, determined the first crystal structures, developed assays to characterize their substrate specificities, defined their functions in vivo, established novel methodologies to assess PGBs, and developed an antibody-enzyme fusion (AEF) to degrade PGBs. Excitingly, the AEF ablates PGBs in vivo in LD mouse models in muscle, heart, and the brain. This AEF is a promising pre-clinical therapeutic for LD with the potential of being the first LD drug.
His laboratory’s work has been recognized by the scientific community via invitations for review articles, talks at national/international symposia, and requests to serve on grant review committees. Dr. Gentry has been recognized for outstanding mentoring with the 2014 NIH IDeA Maciag Award, the 2017 NIH CCTS mentoring award, the 2018 NINDS Story Landis award, and the 2020 Academy of Medical Educator Excellence in Medical Education Award for Mentorship.
Matthew Gentry is Professor & Chair of Biochemistry & Molecular Biology in the College of Medicine at University of Florida. He is a prominent brain metabolism scientist who has made seminal discoveries in the realm of brain glycogen and glucose metabolism and how perturbations in these pathways impact neuro-centric diseases. Matthew has nearly 20 years of experience working on glycogen storage diseases (GSD). He did research on cell signaling and cell division at Syracuse University for his Ph.D. in Molecular Biology (2003) and then worked on the GSD and childhood dementia called Lafora Disease as a postdoctoral scholar in the laboratory of Dr. Jack Dixon at UC-San Diego where he defined the biochemical properties of the genes mutated in the disease. Building on this foundational biochemistry, he has been continuously funded by NIH since 2007 via a K99/R00; multiple R01 grants; a P01; a recent R35 that focuses on Brain Glycogen – Metabolism, Mechanisms, and Therapeutic Potential; other NIH grants; and funding from foundations and industry. He has also been continuously funded by NSF since receiving a NSF CAREER award in 2013 to study the enzymology and structure/function of metabolic enzymes. His lab works on a number of CNS-centric GSDs and the role of glycogen in cancer, focusing on defining disease mechanisms, pre-clinical drugs and clinical biomarkers. He has published >80 scientific papers and holds multiple patents.
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LinkedIn: matthew-gentry
University of Florida Health: gentry-matt
University of Florida Expert File: matthew-gentry
ResearchGate: Matthew-Gentry-3
Member Magazine of the American Society for Biochemistry & Molecular Biology: gentry-named-chair-at-uf
UMR: Progress-On-Hold-Matthew-Gentry
Research Features: Plants provide hope for epilepsy initiative
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