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New Treatment Option Emerges for Huntington's Disease

By: Sai Srihaas Potu

Huntington’s disease (HD) is a neurological condition. It is an inherited disease that happens due to faulty genes. Toxic proteins collect in the brain and cause damage, leading to neurological symptoms. As parts of the brain deteriorate, this affects movement, behavior, and cognition. It becomes harder to walk, think, reason, swallow, and talk. Eventually, the person will need full-time care. The complications are usually fatal.

HD affects one person in every 10,000 or around 30,000 people in the United States. Another 150,000 or more people are at risk of developing the condition. The first signs normally appear between the ages of 30 and 50 years.

HD is caused by a faulty gene (mhTT) on chromosome number 4. A normal copy of the gene produces huntingtin, a protein. The faulty gene is larger than it should be. This leads to excessive production of cytosine, adenine, and guanine (CAG), the building blocks of DNA. Normally, CAG repeats between 10 and 35 times, but in HD, it repeats from 36 to 120 times. If it repeats 40 times or more, symptoms are likely. This change results in a larger form of huntingtin. This is toxic, and, as it accumulates in the brain, it causes damage to brain cells.

Some brain cells are sensitive to the larger form of huntingtin, especially those related to movement, thinking, and memory. It undermines their function and eventually destroys them. Scientists are not sure exactly how this happens.

HD is known as an autosomal dominant disorder. This means that only one copy of the faulty gene, inherited from either the mother or the father, is necessary to produce the disease. A person with the gene has one good copy of the gene and one faulty copy of the gene. Any offspring will inherit either the good copy or the faulty one.

Each child has a 50 percent chance of inheriting the faulty gene. HD can affect several generations. A person who does not inherit the faulty gene will not develop HD and cannot pass it on to their children. A child who inherits the faulty gene will develop HD if they reach the age when symptoms are due to emerge.

Around 10 percent of cases of HD start before the age of 20 years. This is known as juvenile HD (JHD). The symptoms are different and can include leg stiffness, tremors, and regression in learning. Between 30 and 50 percent of people with JHD have seizures.

In recent years, studies have discovered new drugs that can help treat Huntington’s disease. With single drug treatment, researchers at the Ludwig Institute for Cancer Research at UCSD can silence the mutated gene responsible for Huntington’s disease, slowing and partially reversing the progression of the fatal neurodegenerative disorder in animal models.

Researchers suggest the drug therapy, tested in mouse and non-human primate models, could produce sustained motor and neurological benefits in human adults with moderate and severe forms of the disorder.

Huntington’s disease afflicts approximately 30,000 Americans, whose symptoms include uncontrolled movements and progressive cognitive and psychiatric problems. The disease is caused by the mutation of a single gene, which results in the production and accumulation of toxic proteins throughout the brain.

Don W. Cleveland, PhD, professor and chair of the UC San Diego Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, and colleagues infused mouse and primate models of Huntington’s disease with one-time injections of an identified DNA drug based on antisense oligonucleotides (ASOs). These ASOs selectively bind to and destroy the mutant gene’s molecular instructions for making the toxic huntingtin protein.

The singular treatment produced rapid results. Treated animals began moving better within one month and achieved normal motor function within two. More remarkably, the benefits persisted, lasting nine months, well after the drug had disappeared and production of the toxic proteins had resumed.

Beyond improving motor and cognitive function, researchers said the ASO treatment also blocked brain atrophy and increased lifespan in mouse models with a severe form of the disease. The therapy was equally effective whether one or both huntingtin genes were mutated, a positive indicator for human therapy.

Cleveland noted that the approach was particularly promising because antisense therapies have already been proven safe in clinical trials and are the focus of much drug development. Moreover, the findings may have broader implications for other age-dependent neurodegenerative diseases that develop from exposure to a mutant protein product and perhaps for nervous system cancers, such as glioblastomas.

HD has a major emotional, mental, social, and economic impact on the lives of the individual and their families. After diagnosis, a person will normally live for 15 to 20 years, but the duration ranges from 10 to 30 years. A person with JHD will probably live for around 10 years. This form progresses more quickly. The cause of death is often a complication, such as pneumonia or choking. While there is currently no cure, some therapies can help people to manage the condition and improve their quality of life.

Thanks to an explosion of research, our understanding of Huntington’s disease is among the most developed knowledge areas in genetics. Due to continued gaps in our understanding of the pathophysiology of neurodegenerative disorders and the absence of valid, reliable human biomarkers, researchers have not been able to understand more about Huntington’s disease. However, further research will help scientists understand more about the mechanism behind Huntington’s disease which will help them develop reliable treatment options for the disorder.


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2. Don W. Cleveland, Holly B. Kordasiewicz, Lisa M. Stanek, Edward V. Wancewicz, Curt Mazur. Sustained Therapeutic Reversal of Huntington’s Disease by Transient Repression of Huntingtin Synthesis. Neuron. 2012.

3. Foroud T, Gray J, Ivashina J, Conneally PM. Differences in the duration of Huntington’s disease based on age at onset. Journal of Neurology, Neurosurgery, and Psychiatry. 1999.

4. Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, et al. Characterization of the Huntington intermediate CAG repeat expansion phenotype. Neurology. 2013.


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