Transformative Research Awards

These million-dollar research awards, HDF’s largest grants, fund collaborative research teams to create innovative ways to study new pathogenic disease mechanisms and treatment modalities in Huntington’s disease.

Announcing Our 2024 Recipient

The Hereditary Disease Foundation is pleased to announce the recipient of our $1 million 2024 Transformative Research Award. Dr. Andrew Yoo from Washington University School of Medicine in St. Louis and Dr. Osama Al Dalahmah from Columbia University Irving Medical Center will partner on this 2-year grant to advance research on two novel molecules that have potential as therapeutic targets for Huntington’s disease (HD).

Andrew S. Yoo, PhD
Principal Investigator

Osama Al Dalahmah, MD, PhD
Co-Investigator

The Project: Uncovering Huntington’s Disease-Associated Human-Specific Non-Coding Transcripts as Therapeutic Targets

The overall goal of this project is to test if two targets could be therapeutic options for treating HD.

Drs. Yoo and Al Dalahmah have identified bits of genetic message that are only present in people with HD. These genetic bits are called non-coding RNAs. They are pieces of genetic material that the cell never intends to turn into proteins, but they themselves perform regulatory functions throughout the cell. Two such non-coding RNAs, called HD-LINC and HINT, have been identified by the team to only be expressed in people who are symptomatic with HD, suggesting that the presence of these molecules is related to the disease itself and not just the genetic presence of the HD gene.

Drs. Yoo and Al Dalahmah have already generated data that suggests when amounts of targets are reduced, HD features of the cells grown in a dish improve, notably cell death and protein clumps associated with the disease, suggesting the presence of these non-coding RNAs is toxic to brain cells.

In this project, the team will determine if either HD-LINC or HINT have therapeutic potential as a drug target for HD by further examining these molecules in Dr. Yoo’s novel cellular system and human brain tissue obtained by Dr. Al Dalahmah. They will also assess this potential in a mouse model specifically designed to harbor these human-specific non-coding RNAs. Lastly, the team will develop antisense oligonucleotides (ASOs) that target both HD-LINC and HINT that can be advanced toward clinical trials. Ultimately, this proposal will provide go/no-go decision criteria on two non-coding RNAs that would represent a novel class of therapeutic targets for the HD space.

This transformative project approaches the problem of HD by first asking what is changed in the human condition, then uses model systems, like cells and mice, to test if those targets could be therapeutic options. Additionally, the therapeutic target of interest is entirely novel within the HD space. Most therapeutic approaches currently in clinical trials target the genetic message that causes HD. Many preclinical studies are working to target somatic expansion, the perpetual increase of the disease-causing CAG repeat within the huntingtin gene. Drs. Yoo and Al Dalahmah will focus on what stands to be a totally novel target for HD research, non-coding RNAs, advancing truly transformative research for the development of HD therapeutics.

2023 Awards

The 2023 awards were given to two all-star collaborative teams, one led by Dr. Beverly Davidson of the Children’s Hospital of Philadelphia and University of Pennsylvania, and the other led by Dr. Ricardo Mouro Pinto of Massachusetts General Hospital and Harvard Medical School. They each will receive funding of $1 million over the next two years to advance their work toward developing treatments for Huntington’s disease.

Dr. Davidson’s and Dr. Mouro Pinto’s teams each use cutting-edge methods but take different approaches to advance Huntington’s disease research and, if successful, could lead to truly transformative therapies for Huntington’s disease.

Click on the buttons to the right to read the details for each project.

Beverly L. Davidson, PhD
Principal Investigator

Leslie M. Thompson, PhD
Co-Investigator

Jang-Ho John Cha, MD, PhD
Co-Investigator

Dr. Beverly Davidson’s Project

The Project: Translational studies on PIAS1 and MSH3 knockdown for Huntington’s disease

The team is using an adeno-associated virus (AAV) that can be injected into the brain at very small volumes and widely infect cells of the brain. This improves on current approaches that require multiple injections at larger volumes that also infect fewer cells. The team is targeting 2 proteins: MSH3 and PIAS1. MSH3 is involved in a biological phenomenon called “somatic instability,” which is the molecular stutter in the CAG repeat that causes HD to expand over time in vulnerable tissues, particularly the brain. Understanding somatic instability in Huntington’s disease has become one of the hottest topics this decade, as it’s thought to drive disease onset and progression. If it can be controlled, it’s very possible that HD could be halted. PIAS1 is involved in the degradation of the protein that causes HD. Dr. Thompson’s lab was the first to identify PIAS1 as playing a role in HD and has since collaborated with Dr. Davidson on understanding the molecular role of PIAS1 in HD biology. They have shown that by changing levels of PIAS1, mouse models of HD significantly improve.

This project seeks to inject the AAV tools that they’ve created into the brains of primates. These AAVs will change levels of MSH3 and PIAS1, allowing the research team to ask if there is therapeutic benefit in the HD model most similar to humans – primates. They will also change levels of MSH3 and PIAS1 at the same time using their AAV tool in stem cell models and mice. This will allow them to understand the synergistic effect of targeting both proteins at the same time. If successful, this approach would be a “one-and-done” treatment for HD and will directly lead to clinical trials.

Hear about the project from Drs. Davidson, Thompson and Cha themselves during our April 2024 Research Spotlight Webinar: “Developing Transformative Tools: Gene Therapy for Huntington’s Disease.”

Ricardo Mouro Pinto, PhD
Principal Investigator

James F. Gusella, PhD
Co-Investigator

Benjamin Peter Kleinstiver, PhD
Co-Investigator

David R. Liu, PhD
Co-Investigator

Benjamin E. Deverman, PhD
Collaborator

Cathleen Lutz, PhD, MBA
Collaborator

Vanessa C. Wheeler, PhD
Collaborator

Dr. Ricardo Mouro Pinto’s Project

The Project: Therapeutic targeting of somatic CAG expansions with precise CRISPR base editing

The overall goal of this proposal is to permanently halt somatic instability with a one-and-done (gene editing) approach to the brains of mice that model Huntington’s disease. The team will target genes they have identified, MLH3, MSH3, and PMS1, with known roles in somatic instability in HD. The team has strong preliminary data to support the targeting of these specific genes. Previous work by members of the team has demonstrated editing these genes won’t have negative effects, such as causing cancer. They will target these genes using AAVs that contain molecular machinery allowing for CRISPR editing of each of the genes. After mice are treated, they will be analyzed in depth to study the effects of gene editing. Additionally, experiments will be done with cells from HD patients to determine the effects of this technology in human cells.

This project develops genome editing therapeutics that target the cause of CAG repeat expansion in Huntington’s disease. If successful, this work will lead to pre-clinical studies testing the effect of altering MLH3, MSH3, and PMS1 on behavior of mice that model HD.

Hear about the project from Ricardo Mouro Pinto himself during our February 2024 Research Spotlight Webinar: “Using CRISPR for Huntington’s Disease Drug Development.”