Tackling a Disease on a Global Scale: Applying GP2’s Global Genetics Initiative to Advances in Huntington’s Research

     Earlier this semester, Dr. Makarious gave a fantastic talk about her research in The Global Parkinson’s Genetics Program (GP2). During this talk, she discussed the many genes involved in the development of Parkinson's Disease (PD). However, many of the genetic variants known as risk factors for the disease were determined through genetic studies performed almost exclusively in populations of Northern European Ancestry. This has caused a lack of genetic diversity in Parkinson's research that GP2 seeks to correct. GP2 proposes an expansion of genetic research in underrepresented populations, as research has shown that there are significant differences in the genes involved in PD across populations. In gaining a better understanding of the different genotypic variants that contribute to PD, we will be able to deepen our understanding of the disease across populations and create more specialized therapeutics. This will increase equity as treatments and diagnostic tools can be developed with the representation of individuals from diverse backgrounds in mind, rather than being limited by our previous Eurocentric view of the data.

    Recently, there has been a breakthrough in Huntington’s disease treatment through the use of gene therapy. Similar to PD, Huntington’s Disease is a neurodegenerative disease related to genes. However, unlike PD, Huntington’s Disease is known to be caused by a mutation in a single gene, the HTT gene. The wild-type HTT gene encodes for a protein called huntingtin, which functions as a multifunctional scaffold protein helping mediate protein-protein interactions. In the mutant HTT gene, excessive CAG trinucleotide repeats result in a mutant huntingtin protein. Mutant huntingtin interacts differently with proteins, disrupting a variety of crucial cellular functions leading to the development and progression of Huntington’s disease. To address this, researchers have developed a gene therapy that targets the mRNA transcribed from the HTT gene, preventing the production of huntingtin. The treatment uses a viral vector injected into the striatum to deliver DNA encoding miRNA that will recognize, bind, and non-selectively lower the production of huntingtin protein (i.e., both wild-type and mutant huntingtin protein). After a small clinical trial of 29 people with early-stage Huntington’s Disease, participants who received a high dose of gene therapy saw a 75% decrease in disease progression over three years compared with those in the control group. Although additional studies are needed with larger and more diverse populations, this breakthrough offers hope for developing long-term gene-based therapies for the treatment of Huntington’s disease and possibly other neurodegenerative disorders as well.

    Although the promise of this gene therapy is exciting, I cannot help but think about what might happen if we were to apply a similar philosophy as GP2 to this treatment. GP2 emphasizes studying genetic variation across populations to better understand disease risk and promote equitable treatment. I believe applying this approach to the treatment of Huntington’s could be just as valuable as in PD. Of course, this would likely look different as Parkinson’s Disease involves many genes, while Huntington’s is primarily caused by mutations in HTT. However, growing research suggests additional genes, such as FAN1, can play a role in disease onset and severity. This raises the question of whether these genes could influence how patients respond to the therapy. If certain variants stabilize or accelerate a repeat expansion, they could possibly alter the treatment’s effectiveness across individuals or even populations. Although there is a lot more to be done, if researchers could map variations in these genes or find others, perhaps they could predict whether certain populations might respond differently to gene therapy. These results could possibly help ensure that the treatments developed for Huntington’s disease are equitable and do not solely serve one demographic.

References:

Blauwendraat, Cornelis, et al. “Tackling a disease on a global scale, the global Parkinson’s Genetics Program, GP2: A new generation of opportunities.” The American Journal of Human Genetics, vol. 112, no. 9, Sept. 2025, pp. 1988–2000, https://doi.org/10.1016/j.ajhg.2025.07.014.

Dolgin, Elie. “Huntington’s disease treated for first time using gene therapy.” Nature, vol. 646, no. 8083, 2025, pp. 15–15, https://doi.org/10.1038/d41586-025-03139-9.

Jones, Lesley, et al. “Special issue: DNA repair and somatic repeat expansion in Huntington’s disease.” Journal of Huntington’s Disease, vol. 10, no. 1, 30 Jan. 2021, pp. 3–5, https://doi.org/10.3233/jhd-219001.

uniQure. “Phase I/II Clinical Trial of AMT-130: Programs & Pipeline.” uniQure, www.uniqure.com/programs-pipeline/phase-1-2-clinical-trial-of-amt-130.