Huntington’s Disease

Overview

Huntington’s disease (HD) is an inherited, fatal degenerative brain disease that affects movement, cognition, and behavior. HD results from a mutation in one gene—the Huntingtin gene—which produces a toxic protein that ultimately kills nerve cells. HD affects 1 in every 10,000 people. [1] Over 30,000 people in the United States have been diagnosed with Huntington’s disease. Due to the inherited nature of the gene mutation, another 150,000 have a 50% chance of developing the disease since they had a parent with HD. HD typically strikes in a person’s thirties, and leads to death within 15 years. [2]

HD carries an enormous societal and familial cost; the rapid and debilitating nature of the disease requires extensive caregiving. The disability and loss of earning power and personal freedom resulting from HD is devastating emotionally and financially. Individuals are struck in the prime of life, at a point when they are most productive and have their highest earning potential. As the disease progresses, individuals require institutional care, which comes with exorbitant financial costs. [3]

Early symptoms of HD are often quite subtle mental and emotional changes, proceeding to issues with coordination and movement. A hallmark symptom of Huntington’s disease is chorea: uncontrollable and often painful involuntary movements. The cognitive and psychiatric symptoms of HD become increasingly debilitating over time, eventually leading to inability to carry out daily tasks or take care of one’s family, depression, memory problems and impaired judgment. Delusions and hallucinations may occur. Symptoms of the disease can worsen between generations of individuals with HD, leading to earlier onset and increased severity. [4]

These symptoms continue to worsen until death, usually from related medical problems. Existing drugs can reduce the involuntary movements and some psychiatric symptoms, but do nothing to slow the inexorable progression of the disease.

As Dr. Vicki Wheelock, a physician-scientist and HD specialist at the University of California, Davis, notes:

“[Huntington’s disease] touches all races and socioeconomic levels. The financial burdens are in the billions, the emotional costs are immeasurable, and right now there is no cure. Our [California Institute for Regenerative Medicine] grant enables us to greatly accelerate our work toward developing a safe and effective cellular therapy for Huntington’s disease. As a physician who has witnessed the tragedy of this illness over and over again, I know that this very generous grant represents an important turning point in our efforts to overcome this disease. The award gives us the hope of developing a disease-modifying treatment for HD and the optimism of finding a cure.” [5]

Progress Toward a Cure

California’s stem cell agency, the California Institute for Regenerative Medicine (CIRM)—formed in 2004, when voters passed Proposition 71: the California Stem Cell Research and Cures Act—has awarded more than $26 million in funding to researchers studying Huntington’s disease.

At the University of California, Irvine, Dr. Leslie Thompson is leading a network of teams throughout California and across the country to identify and test stem cell treatments for Huntington’s disease. With more than $10 million in funding fromCIRM, Thompson and her team have worked to “reprogram” skin cells of HD positive patients into induced pluripotent stem cells (iPSCs). This “disease in a dish” model has uncovered new avenues that could lead to drugs to treat HD. [6]

Currently, Dr. Thompson and her colleagues are working on basic and early-stage transitional studies to develop a cell-based strategy, using embryonically-derived neural (brain) stem cells, to treat areas of the brain that are susceptible to HD.

Thompson’s group has identified a highly promising neural stem cell line that shows disease-modifying activity in HD mice. These neural stem cells are derived from human embryonic stem cells at a clinical grade manufacturing facility at UC Davis sponsored by CIRM. The researchers will conduct essential preclinical efficacy and safety studies in HD mice with these cells. [7] Their goal is to finalize work that will lead to a pre-Investigational New Drug (IND) meeting with the Food & Drug Administration (FDA) and a path forward for clinical trials with the neural stem cells.

“These stem cell lines offer a possible long-term treatment approach that could relieve the tremendous suffering experienced by HD patients and their families,” said Thompson, who is also affiliated with UCI’s Institute for Memory Impairments and Neurological Disorders (UCI MIND) and with the Sue and Bill Gross Stem Cell Center.

Another CIRM funded research team, headed by Dr. Vicki Wheelock and Dr. Jan Nolta at UC Davis, hopes to treat Huntington’s Disease by implanting stem cells that deliver a growth factor—called Brain Derived Neurotrophic Factor, or BDNF—into the brain. While this special type of mesenchymal stem cell will not repopulate the brain cells that are destroyed in HD, BDNF offers important support to the affected brain region. Scientists are able to engineer mesenchymal stem cells, normally a kind of connective, support cell, to secrete BDNF. In animal studies, these modified cells are then injected into the brain, where they stimulate genesis of new brain cells and reduce some of the HD-associated behavior deficits. [8] If this work translates into human patients, these stem cells can be used as “delivery vehicles” to offset brain degeneration caused by HD.

This BDNF delivery method has shown proof of safety in mice and resulted in major reductions in their behavioral deficits. Human clinical trials to further this effort may begin soon. BDNF is a highly promising candidate for the treatment of HD, as it has been shown to prevent cell death and to stimulate the growth and migration of new neurons in the brain in transgenic mouse models. Post-mortem analysis of brain tissue in HD patients has shown abnormally low levels of BDNF, suggesting that a deficit or absence of this growth factor is linked to the progression of HD. [9]

UC Davis’ success in using the stem cell approach serves as an important stepping-stone to obtaining U.S. Food and Drug Administration approval to test the therapy’s safety and efficacy in human patients with the disease. If successful, the team’s genetically modified BDNF cells would set a precedent for stem cell-based neurotherapeutics and could potentially be modified for other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease, and some forms of Parkinson’s disease. [10] Further, these cells could provide a platform delivery system for future studies involving corrective gene editing strategies. [11]

The planned UC Davis trial to test HD treatments will target patients in the earlier phases of HD, before the illness’s full impact takes its toll. The team believes that mesenchymal stem cells represent effective delivery vehicles because they move well through tissue, and can produce high levels of growth factor for uptake by the damaged neurons. In preparation for a Phase I clinical trial with HD patients, the Huntington’s disease team is carefully testing its proposed cellular infusion therapy for safety. [12]

As Frances Saldana, a patient advocate whose husband and three children were diagnosed with HD, notes:

“Much has been accomplished in the area of HD scientific discoveries, but we did not have the treatment for HD in time for [my daughters] Margie and Marie. Their battle is now over, but for Americans for Cures, our battle continues. My son fights for his life every day, although the end of his fight is near. It is not too late for future generations. We need to continue supporting stem cell research, not just for Huntington’s disease, but for all who suffer from incurable and devastating diseases. Americans for Cures is the strongest defense I have in my hope for a treatment for Huntington’s disease.”

Selected disease and research progress information provided by the California’s stem cell research funding agency, the California Institute for Regenerative Medicine (CIRM). Visit www.cirm.ca.gov for more updates.

Featured Image: HD Advocates Daniel Medina and Judit Serra at the 2015 HD-CARE Symposium.

Footnotes

[1] Ring, Karen.   “CIRM-funded clinical trial for spinal cord injury reports promising results.”  31 August 2015.  California Institute for Regenerative Medicine. Web.  https://blog.cirm.ca.gov/2015/08/31/cirm-funded-clinical-trial-for-spinal-cord-injury-reports-promising-results/

[2] Author, No.  “Huntington’s Disease: Progress and Promise in Stem Cell Research.”  California Institute for Regenerative Medicine.  Web.  Accessed 13 February 2016.  https://www.cirm.ca.gov/our-progress/video/huntingtons-disease-progress-and-promise-stem-cell-research

[3] Thompson, Leslie.  “A hESc-based Development Candidate for Huntington’s Disease.”  California Institute for Regenerative Medicine.  Web.  Accessed 16 February 2016.  https://www.cirm.ca.gov/our-progress/awards/hesc-based-development-candidate-huntingtons-disease

[4] Author, No.  “Huntington’s Disease.”  University of California Irvine MIND.  Web.  Accessed 16 February 2016.  http://mind.uci.edu/alzheimers-disease/other-dementias/huntingtons-disease/

[5] Casey, Charles.  “Huntington’s disease research fueled by $19 million from stem cell agency.”  26 July 2012.  University of California Davis Health System.  Web.  Accessed 12 February 2016.  https://www.ucdmc.ucdavis.edu/publish/news/newsroom/6809

[6] Loughlin, Sandra.  “UCI team gets $5 million to create stem cell treatment for Huntington’s disease.”  26 March 2015.  University of California Irvine News.  Web.  Accessed 16 February 2016.  https://news.uci.edu/health/uci-team-gets-5-million-to-create-stem-cell-treatment-for-huntingtons-disease/

[7] Id.

[8] Nolta, Jan et al.  “Human Mesenchymal Stem Cells Genetically Engineered to Produce Brain derived Neurotrophic Factor Improve Outcomes in Huntington’s disease Models.”  14 January 2016.  Molecular Therapy.  Web.  Accessed 13 February 2016.  http://www.nature.com/mt/journal/vaop/naam/abs/mt201612a.html

[9] Id.

[10] Id.

[11] Id.

[12] Casey, Charles.  “Huntington’s disease research fueled by $19 million from stem cell agency.”  26 July 2012.  University of California Davis Health System.  Web.  Accessed 12 February 2016.  https://www.ucdmc.ucdavis.edu/publish/news/newsroom/6809

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