Massachusetts General Hospital has the largest and most diverse group of laboratories working on Huntington's Disease in the world.

Huntington’s Disease Research
at MassGeneral Institute for Neurodegenerative Disease

Overview

Our cadre of scientists and physician-scientists are working to solve the riddle of this devastating disease.  MIND facilitates all aspects of research on HD, from molecular investigations of disease mechanisms, to screening potential drugs in test tube models, and testing compounds in preparation for human clinical trials.

Genetics

MGH researchers found the HD gene mutation in 1993 which led to the development of transgenic mice – “mouse models” in 1996.  These mice have a portion of the HD gene and develop symptoms and the other neurological hallmarks of the disease.  MIND has an animal laboratory that houses colonies of these mice for study, and we also collaborate with scientists around the world who have developed mouse models.   Ongoing genetic studies in the MGH Center for Human Genetic Research directed by James Gusella, PhD, include finding genetic modifiers that influence the age of onset of HD and the progression of the disease.  These modifying genes many give us clues about how to delay onset or slow progression.

Molecular Research - Basic Science Leads to Important Discoveries

MIND researchers were among the first to map out the mechanisms underlying the pathophysiology of Huntington’s disease.  We are grateful to patients and their families who have made generous donations of post-mortem brain tissue that allows us to study human brain. Dr. Anne Young’s studies in the neuroanatomical and neurotransmitter organization of the basal ganglia of the brain laid the foundation for the idea that certain groups of brain cells are particularly vulnerable in HD.

Dr. Marian DiFiglia has also been studying HD for more than twenty years. Among her discoveries were that the size of the polyglutamine (CAG) repeat in the gene predicts the course of the disease, and that aggregation of mutant huntingtin (the protein encoded by the gene) is a hallmark of its neuropathology.  She currently leads a multidisciplinary research team investigating the role of the HD mutation in the molecular and cellular events leading to neurodegeneration.

Dr. Jang-Ho Cha’s laboratory first described mRNA alterations in transgenic HD mice, leading to the hypothesis that gene transcriptional dysregulation is a central mechanism in HD.  Transcription is the process by which genes encode proteins that are the building blocks for the function of all cells in the body, and this finely tuned process is disrupted in HD.  His group’s analysis showed that the mutant HD protein disrupts a number of critical cellular processes which are especially important for the normal functioning of brain cells.  He is using state-of-the-art technology to understand how abnormal proteins interact with DNA and send signals to turn the wrong genes on and off, ultimately resulting in brain cell death.  He is also taking these techniques perfected in HD to the other neurodegenerative diseases, with the ultimate goal of finding smarter drugs that inhibit the action of specific gene-altering molecules.

Dr. Young’s lab at MIND was the first to apply the new technology of large-scale DNA micro-array analysis to a human neurologic disease.  This technology allows researchers to analyze DNA from the post-mortem brains of patients with Huntington’s disease, instantaneously measuring what happened to 11,000 genes, thus providing a “snapshot” of all the perturbations that the mutant HD gene causes.  This group’s findings corroborate the theory of gene transcription problems in HD, and point to several new areas of investigation.

Dr. Dimitri Krainc’s research involves deciphering the molecular pathways of transcriptional deregulation and mutant protein accumulation in HD. His group has shown that deregulation of transcription by mutant huntingtin leads to defects in energy metabolism and dysfunction of neurons that are most vulnerable to metabolic stress in HD.  

Another recent initiative in Dr. Krainc's laboratory has been to define the pathways responsible for the clearance of mutant proteins that cause Huntington's and Parkinson's disease, with the goal of finding common pathways that can be enhanced to contribute to therapies for these diseases.

Dr. Steven Hersch’s laboratory is exploring how the huntingtin protein, oxidative stress, DNA injury, and transcriptional dysfunction interact to understand the sequence of molecular events that lead to neuronal dysfunction and death and to discover new therapeutic targets. A unifying hypothesis that is gradually taking shape is that huntingtin’s interactions with oxidatively damaging metals directly injures DNA and other nuclear molecules, triggering coordinated alterations in gene transcription. Accordingly, antioxidants, transcriptional modulators, and metal chelators are all advancing as candidate therapeutic agents for HD.

Dr. Anne Young’s lab has a longstanding interest in the role of neurotransmitters – the brain’s electrical system used to communicate between cells.  Her group has been investigating how metabotropic glutamate receptors can become over-excited and burn out, eventually causing the destruction of brain cells.  Their group hopes to unlock the potential for protecting the degradation of these receptors.

Biomarkers

As we develop drugs for diseases like HD that were previously considered untreatable, it becomes essential to find ways to easily diagnose disease at its earliest stage as well as assess whether new drugs are having the intended effect.  MIND scientists are seeking biomarkers – blood, fluid or brain measurements– that will provide important information about the progression of HD and allow us to measure changes over time and in response to therapy.

Dr. Steven Hersch and Dr. Diana Rosas have developed a comprehensive multidisciplinary effort to develop, assess and validate biomarkers for HD with collaborators at the Brigham and Women’s Hospital, MIT, Bedford Veteran’s Administration Hospital and the University of Rochester. This effort utilizes clinical information, blood samples, and neuroimaging collected from patients at the MGH HD Clinic and from dozens of collaborating centers in North America and Europe.

This program, supported by NIH, is discovering biomarkers that can detect biological and brain changes in HD before clinical symptoms occur, that can monitor progression of disease, and that show a response to treatments.  These biomarkers will be tested in multi-center observational and treatment trials in both premanifest and symptomatic HD subjects. We are also studying biomarkers in mouse models of HD to better understand them at a molecular level.

Dr. Diana Rosas’ laboratory is using sophisticated MRI imaging and analytic techniques to understand how HD starts long before symptoms occur, to understand how involvement of different areas of the brain are responsible for the different symptoms that occur, and  to track  the progression of HD.  These methods have shown promise as a way to monitor whether brain deterioration can be slowed by potential neuroprotective treatments. Her work has demonstrated that many brain regions contribute to the symptoms of HD and has sparked a paradigm shift away from the concentration on  preventing disease in the striatum towards preventing disease in the entire brain.

In Dr. Dmitri Krainc’s lab, a genome-wide expression analysis in patients with HD has identified potential blood biomarkers.  A specific set of genes was identified in blood samples that distinguished individuals with HD from controls.  These alterations in gene expression correlate with disease progression to the symptomatic stage and respond to experimental treatment.  Such markers may be of predictive value in clinical trials.

Drug Discovery

At MIND, discoveries in the laboratory have immediate implications for development of potential therapeutics.  MIND houses a high-throughput drug screening facility directed by Dr. Alex Kazantsev, that allows researchers to test their ideas with compounds that may slow or halt disease progression.  The first step is to develop a petri-dish model of the disease mechanism with which drug interactions can be measured -- this is called assay development.  Once an assay is developed and refined, the lab’s robotic screening equipment can test MIND’s library of 40,000 drug-like compounds to see which produce desired results in the cell-based model of the disease.  These procedures previously were done by hand, but MIND’s high tech equipment now allows it to be done methodically and quickly.  Any “hits” from the screening then undergo further testing and refinement before they are tried on animals.

MIND’s drug discovery efforts have been highly successful, with several promising compounds identified through high throughput screening.  One compound, “C28” has been through rigorous testing and modifications and has shown success in HD mouse models.  This is the first time that a completely novel compound (not based on existing medications) has made it through the numerous stages of testing to enable clinical trials on transgenic HD mice.   Other compounds are in the pipeline, and assays are in development to quickly find other small compounds that hold promise to stop or slow the relentless progression of HD.

Dr. Marian DiFiglia is working on another approach to treating HD.  Her collaborative efforts are directed at therapies to completely shut down the mutant Huntington’s disease gene, protecting brain cells from the lethal form of protein encoded by the gene.  This approach is called RNA interference, a cutting edge technology which works by silencing the mechanism for the production of a gene’s protein. Dr. DiFiglia has shown that injecting silencing RNA’s directed at the HD gene can reduce mutant protein and restore some functioning in mice. Further work is needed before this approach can be used in humans, but the principle has now been shown to be feasible.

Testing Therapeutics

Dr. Marian DiFiglia is working on another approach to treating HD.  Her collaborative efforts are directed at therapies to completely shut down the mutant Huntington’s disease gene, protecting brain cells from the lethal form of protein encoded by the gene.  This approach is called RNA interference, a cutting edge technology which works by silencing the mechanism for the production of a gene’s protein. Dr. DiFiglia has shown that injecting silencing RNA’s directed at the HD gene can reduce mutant protein and restore some functioning in mice. Further work is needed before this approach can be used in humans, but the principle has now been shown to be feasible.

Dr. Steven Hersch leads the testing of potential therapeutic compounds in transgenic mouse models of HD.  Many of these compounds derive from MIND’s basic science studies and drug discovery efforts. These therapeutics directly translate the latest findings into potential targets for treatment, taking the science from the laboratory bench right to the bedside.

Dr. Hersch is currently testing antioxidant, energy buffering, transcription modifying, metal chelation, proteolysis modifying, and neurotransmission altering drugs in HD mice. The testing process is challenging because Huntington’s disease mice are fragile, making them expensive to acquire, house and “treat”.  In addition, each compound must be tested in many different ways, examining several modes of administration and dosing levels, as well as various combinations of different compounds.

Many compounds have been shown to slow the neurologic deterioration of HD mice and are moving forward to clinical trials in patients.  There is more hope than ever before that an effective “cocktail” of drugs will soon be available for HD patients.

Collaboration on Drug Development

One of the goals of the creation of MIND five years ago was to enlist interest from pharmaceutical and biotech companies to work on these difficult diseases, especially those like HD which are “orphan diseases”-- affecting relatively few patients.  Our goal became a reality when MIND signed a groundbreaking agreement with Novartis, a world leader in drug discovery.  The agreement brings together teams from MIND, MIT and Novartis to work collaboratively on Huntington’s disease therapies.  It is the first time a large pharmaceutical company has made a substantial commitment to tackle Huntington’s disease, bringing intellectual, scientific, and financial resources to the research, including Novartis’s formidable drug compound library.  All the partners believe the collaboration will accelerate the process of finding and testing new drugs.

Clinical Studies

Many clinical research studies and therapeutic trials for HD are conducted in the Neurology clinical research centers associated with MIND. Dr. Steven Hersch, Dr. Diana Rosas, and Dr. Merit Cudkowicz are the principal investigators of studies initiated here or site investigators for academic and industry sponsored trials initiated elsewhere. Studies initiated at MGH include large multi-center Huntington Study Group trials of the potential neuroprotective therapies minocycline, coenzyme Q10, creatine, and phenylbutyrate. Dr. Rosas and Dr. Hersch have also initiated the first therapeutic trial in HD subjects who are not yet symptomatic, with the goal of finding a treatment to delay the onset of disease.

Find out more about clinical studies on the Partners Clinical Trials Huntington's Disease page.

Resources for Parkinson's Disease and Research

Hereditary Disease Foundation

Huntington Study Group

Huntington’s Disease Advocacy Center

Huntington’s Disease Society of America (HDSA)

National Institutes of Health

New England Chapter, HDSA

Stanford HOPES

The HD Lighthouse

The Huntington Project