Jong-Min Lee, PhD
Assistant Professor of Neurology, Harvard Medical School
Research Staff, Massachusetts General Hospital
Computational and Systems Biology to Study Huntington’s Disease, Its Modifiers, and Precision Medicine Strategies

Huntington’s disease is caused by a dominantly inherited expanded CAG trinucleotide repeat in the huntingtin gene that is both necessary and sufficient to cause clinical manifestation. The size of the expanded huntingtin CAG repeat largely determines the age at onset of neurological symptoms. However, the size of the expansion does not perfectly predict individual age at onset, and unexplained variance shows familial segregation, strongly suggesting the existence of genetic disease modifiers. In order to identify human genetic factors capable of delaying or hastening age at onset of symptoms, we as part of the international GeM-HD Consortium capitalized on the power of genome-wide association (GWA) analysis to compare naturally occurring single-nucleotide polymorphisms (SNPs) and age at onset unexplained by the CAG repeat size. In addition, based upon the recognition that mutant huntingtin is the trigger of Huntington’s disease, we are developing perfect allele-specific CRISPR/Cas gene silencing strategies to permanently inactivate the gain-of-function mutations. Our CRISPR/Cas strategies do not target the disease-causing mutations, but aims at haplotype backbone containing the mutation in an allele-specific fashion. Our CRISPR/Cas strategies are broadly applicable because they do not depend on the sequence, size, and location of disease mutation. Our multi-disciplinary approaches to study modifiers and gene targeting approaches are significantly contributing to the development of precision medicine strategies for Huntington’s disease and other neurological disorders.