Hope for Huntington’s Disease: Could gene therapy be the answer?
- Deepti Kumar
- 1 hour ago
- 3 min read
Photo credit: wix.com
What is Huntington’s Disease?
Huntington’s Disease (HD) is a rare genetic disorder that causes progressive brain cell death impacting movement, behavior and cognition. It is caused by a mutation in the Huntington (HTT) gene and is inherited in an autosomal dominant manner. According to the Genetic and Rare Disease Center (GARD) there are fewer than 5000 people in the US with Huntington’s disease. Most people who inherit the mutation are normal for decades, then develop uncontrolled movement (chorea), behavioral and cognitive symptoms. As the disease progresses it leads to severe impairment and death.
Root cause of HD: The DNA triplet code gone wild
The genetic cause of HD lies in the HTT gene that has a DNA triplet repeat CAG of variable length. In most people, this DNA triplet repeats itself 15-30 consecutive times, but people with HD inherit 36 or more CAG repeats. Also, interestingly longer CAG repeat leads to early onset of HD although with high inter-individual variability. This triplet code gone awry leads to production of toxic form of the Huntington protein, that is thought to damage the brain cells.
Hurdles to finding a cure
In 1993, researchers discovered that the expanded CAG repeat in the HTT gene causes HD. A lot of questions still remain unanswered.
Why neurodegeneration in the HD is so cell type specific in the brain?
Why the HD symptoms remain latent for years before manifesting later in life?
How inheriting more than 36 CAG repeats lead to neurodegeneration later in life?
Therapies have focused on the HTT protein with little success. Researchers are shifting their focus on the DNA/RNA regulatory machinery with the hope to slow down the progression of the disease.
Quest for a cure: turning to gene therapy
AMT-130 a one-time gene therapy drug manufactured by uniQure shows potential in phase I/II clinical trials. AMT-130 belongs to a class of Huntington lowering drugs, delivered directly into the brain through a surgical procedure. The treatment aims to halt the production of the toxic Huntington protein, by targeting the messenger RNA that carries the instruction from the DNA to make the toxic protein. The AMT-130 uses an artificial micro-RNA (a class of small RNA molecules used to regulate gene expression) packaged in a harmless Adenovirus 5 (AAV5) vector to silence the Huntington gene. The trial included only 29 participants with some receiving high dose and some receiving a low dose of AMT-130. The initial results from the trial are promising with 75% slower disease progression seen in patients who received high dose of AMT-130, three years following the drug administration. The drug seems to be well tolerated with minimal side effects, related mostly to surgical procedure. These side effects were resolved in the affected patients.
What lies ahead?
While the initial results are promising the road ahead is long. The therapy is not yet approved by the FDA. UniQure is seeking accelerated approval for the therapy. Despite the optimism challenges still remain regarding accessibility and affordability to a large number of people with HD. The logistics of delivering a one-time gene therapy drug surgically will be complicated and would require proper planning, organization and scaling up the production of the drug. It is worth mentioning the courage of the 29 participants to have a drug delivered surgically into their brains when so little was known regarding the side effects. Despite the challenges, the findings from the AMT-130 trial are a huge step forward in the quest to slow done or stop the progression of this debilitating disease bringing hope to the HD community.
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