Landmark HD gene therapy trial begins

Mon June, 29th 2020

The world’s first Huntington’s gene therapy trial is underway, testing a one-off treatment that could slow the progress of the disease for years or even decades.

Two people with HD have been the first to be treated as part of the trial in the United States, it was announced earlier this month.

Developed by Dutch-American company uniQure, the drug, called AMT-130, is packaged inside a harmless virus and delivered deep into the brain via neurosurgery.

The aim is for it to enter brain cells and inhibit the production of the mutant huntingtin protein that is harmful to neurons and is the cause of the disease.

After just one surgical procedure, researchers hope the drug will keep working indefinitely and slow the progress of the disease for many years.

Huntington’s Victoria CEO Tammy Gardner said the start of the trial was a landmark moment in HD clinical research.

“There is a lot to be optimistic about for the community when it comes to research right now,” she said.

“We can’t get out hopes up too high, but this is just another example of the level of focus on the disease by the international research community and biomedical companies that we hope will really pay off in the form of safe and effective treatments.”

The uniQure drug has been shown to reduce huntingtin levels in pre-clinical animal studies and improve signs of the disease. The Huntington’s Disease Society of America said, based on that data, that it was optimistic about the potential of the gene therapy treatment to alter the course of the disease.

uniQure said in a news release that one patient had been treated with AMT-130 and the other, who is in the control group, had undergone more superficial imitation surgery.

Those two people will be observed for 90 days before decisions about continued dosing of the next patients are undertaken.

In total there will be 26 participants in the phase I/II trial – 16 people will receive the drug during surgery that can take eight to ten hours. 10 people will not receive the drug but will undergo imitation surgery (which is less invasive) so they are not aware they haven’t received it.

For 18 months, all participants will undergo periodic neurological exams, lumbar punctures to examine huntingtin levels in their cerebrospinal fluid, cognitive and psychiatric testing and imaging tests. For three and a half years after that they will have yearly visits to evaluate the same measures.

The uniQure gene-therapy clinical trial is looking to find a safe dose of the drug and ensure there are no major negative side-effects. Researchers will also examine how the body processes the drug and then the impact it has on the progress of the disease.

Gene therapy and Huntington’s

Genes are regions of DNA that code for proteins the body needs. A failure to produce normal levels of functional protein due to a defective gene cause disorders like HD.

The uniQure drug AMT-130 is a piece of man-made genetic code called a microRNA. The aim is to insert it once into brain cells to interrupt the production of the mutant protein which damages the brain of people with HD.

If it works as intended, the message from the neuron that contains the faulty HD gene to make the mutant protein will be constantly counteracted by a new set of instructions to delete that message.

That makes the approach different from other clinical trials underway now. They are also aiming to reduce the production of the mutant huntingtin protein, but via regular doses of a drug, rather than a one-off treatment.

The unanswered question that remains with all these trials is whether a reduction in the mutant huntingtin protein (measured in the cerebrospinal fluid that runs along the spine and into the brain) actually translates into a slowing of the progress of the disease.