A handful of British Columbians are helping test a new “gene silencing” drug designed to halt production of a toxic protein that causes brain wasting in Huntington Disease.
A clinical trial now underway to prove the safety of the experimental drug ISIS-HTT will include 36 patients with very early symptoms of the disease.
“This is a brand new technology that is just now being applied to humans,” said Blair Leavitt, director of the Centre for Huntington Disease (CHD) at the University of British Columbia.
The active ingredient in the drug consists of strands of artificial DNA that bind selectively with RNA “messenger molecules” that are created when the huntingtin gene is activated, preventing production of the lethal protein.
The gene-silencing mechanism for the drug was discovered about 15 years ago and earned a Nobel Prize for Andrew Fire and Craig Mello in 2006. Researchers believe the technique can be applied in therapies for other genetic disorders.
“You can target pretty much any gene in the body with a specific set of codes and that’s what makes this therapy so powerful,” said Leavitt. “You can build a sequence of nucleotides that are present in one gene and nothing else, so they only bind to that RNA and they only degrade that RNA. So, very selectively, you can turn off a gene.”
The technique has been shown to work on primates and mice, including successful trials at UBC’s Centre for Molecular Medicine and Therapeutics by Michael Hayden, Canada Research Chair in human genetics and molecular medicine.
“We’ve seen in monkeys that the drug can be taken up by brain cells and that it can turn off the gene,” said Leavitt. “This is our first trial on humans, so our main goal is safety.”
The drug will be injected — in small amounts at first — into the cerebrospinal fluid that surrounds the spinal cord and the brain.
Researchers will monitor levels of mutant huntingtin protein in the spinal fluid of patients and assess participants for involuntary movements, dementia and other symptoms characteristic of Huntington Disease.
The trial is being conducted in six locations in Europe and Canada. Only patients already under care at UBC’s CHD are eligible to participate in the local trial.
“This is the first gene-silencing drug that we have; it’s now in safety trials and it is incredibly promising,” said Bev Heim-Myers, executive director of the Huntington Society of Canada. “This is the first drug that will address the root cause of Huntington Disease.”
Until now, therapies available to Huntington patients have been limited to treating symptoms of the disease, which so far cannot be slowed or cured.
“(Gene-silencing) drugs have great potential for many neurodegenerative diseases because they can be tailored to modify the production of any target protein,” said Frank Bennett, senior vice-president of research at Isis Pharmaceuticals, which is developing the drug.
“Huntington is ideally suited to this innovative therapeutic technology because it comes with genetic certainty: everyone with the mutant gene will get the disease at some point.”
However, the inevitability of Huntington raises the spectre of genetic discrimination and may limit who participates in research, according to Heim-Myers.
“Potential participants need a test to detect whether they have the mutation, which could expose them to genetic discrimination by employers and insurers,” she said. “It is critical that we protect the genetic information of people with Huntington, Alzheimer’s and all genetic diseases so that this kind of research can move forward.”
Canada is the only G7 country that does not protect genetic information, she noted.