After careful Scientific Advisory Board review, HDSA is excited to award the Berman-Topper Family HD Career Development Fellowship to Dr. Eduardo Silva Ramos (Max Delbrück Center for Molecular Medicine, Berlin, Germany) and Dr. Adys Mendizabal (University of California at Los Angeles). These prestigious fellowships, made possible in part by the generosity of the Berman and Topper families, provide up to $80,000 of funding per year for three years to young scientists and clinicians who desire to make Huntington’s disease (HD) part of their long-term career plan. Dr. Ramos’ project, entitled “Characterization and targeting a novel HTT interacting E3 ligase protein complex,” will attempt to understand how the huntingtin protein is regulated in the body and what can be done to better target it for therapeutic development. Dr. Mendizabal’s research, entitled, “HD epidemiology, healthcare utilization, and outcomes in racially and ethnically diverse populations in the US,” will help us determine the actual prevalence of HD in racially diverse communities and how they utilize HD healthcare options.
Possible Pathways to Halt HD: Protein Modulators of CAG Repeat Expansion
Huntington’s disease is caused by a CAG repeat expansion in the huntingtin gene. We usually think of the CAG repeat number as being fixed, but research shows that over the course of a person’s lifetime, CAGs can expand in some brain cells. This may result in more damage and cause symptoms to appear earlier. This process, known as somatic expansion, is regulated by other proteins in the body, and HD scientists are developing therapeutic interventions to slow down repeat expansion and delay onset of symptoms in Huntington’s disease. An article recently published in the Journal of Nucleic Acids Research, co-authored by HDSA Human Biology fellow, Dr. Ricardo Mouro-Pinto, investigated one of these proteins. This study explored the role of MLH3, a repair protein that identifies errors in the process of copying DNA.
By inducing a small mutation in a region of the MLH3 protein, researchers were able to stop CAG repeat expansion in mouse models of Huntington’s Disease. To determine if the same result could be accomplished with a pharmaceutical intervention, drugs that can modify the amount of MLH3 protein in cells, called splice switching oligonucleotides (SSOs) were administered to HD cells grown in a dish. The SSOs successfully disabled production of the same region of MLH3 that scientists targeted in HD mice to halt CAG repeat expansion. This study’s conclusions support the viability of MLH3 as a therapeutic target in HD. Treatment strategies that target somatic repeat expansion have the potential to delay disease onset in HD as well as other trinucleotide repeat disorders.
Help 4 HD: Gene Positive vs Symptom manifestation—When Should We Diagnose?
In a recent episode of the podcast “Help 4 HD,” host Lauren Holder was joined by neuropsychiatrist Dr. Hugh Rikards to discuss diagnosing HD. Although the genetic mutation that causes Huntington’s disease (HD) can be detected long before the onset of symptoms, diagnosis of manifest HD tends to treat the disease like a switch that is suddenly flipped on. In this conversation, Dr. Rikards and Lauren walk through the pros and cons of viewing HD as a continuum rather than a line in the sand and discuss what early diagnosis could mean for the start of HD care, medical coverage, clinical research opportunities, and proactive HD care. Listen to the full episode here.