ARTICLE IN BRIEF
Three different gene editing techniques have successfully inhibited or silenced the mutant huntingtin gene implicated in Huntington’s disease.
CHICAGO—Gene silencing and editing techniques aimed at modifying the mutant huntingtin gene (HTT) to reduce levels of the protein promise to change the landscape for patients with Huntington’s disease (HD), according to several reports presented at the Society for Neuroscience annual meeting here in October.
Scientists at the University of British Columbia’s Centre for Molecular Medicine and Therapeutics (CMMT) identified eight of the most common genetic variations on the HTT gene associated with HD and tested specialized antisense oligonucleotides (ASOs) in blood cells from HD patients to assess whether the drugs can silence, or turn off, the mutated gene and reduce levels of the toxic huntingtin protein. The drugs work by binding to the messenger RNA and inducing degradation of the transcript, preventing synthesis of the mutant protein.
Michael Hayden, MD, PhD, and his colleagues at the CMMT performed genetic analyses of thousands of HD patients and healthy controls to identify variations on the HTT gene that are common among HD patients. With these specific variations in hand, they developed ASOs that target each one of these genetic sequences and delivered a combination of ASO molecules to HD animals to see whether they work to reduce the toxic huntingtin protein. The normal huntingtin protein, critical for brain cells throughout life, is not targeted in this approach.
“We identified eight single nucleotide polymorphisms (SNPs) that are enriched on the mutant allele,” said Nicholas Caron, PhD, a postdoctoral fellow in the Hayden laboratory who presented the latest data on this work. “We wanted maximum coverage for HD patients. The panel of ASOs we are now identifying and testing could ultimately help treat up to 85 percent of the HD population. We hope we can identify ASOs for each haplotype so we can tailor the medicine for an individual patient.
“We design ASOs to bind to that specific sequence on the allele and only silence the mutant copy,” Dr. Caron explained. “The difference in our approach is that other ASOs target the wild-type and mutant alleles. But the wild-type protein is important for neuronal health.”
Dr. Hayden’s team has evaluated ASOs that target one of the HD SNPs they identified, and they are now using a potent and well tolerated ASO in animals to see whether it is effective at reducing the mutant huntingtin protein. They are developing a panel of ASOs targeting HD SNPs specific to the three most common HD HTT haplotypes.
Lowering mutant huntingtin in animal models of HD has proven effective at reducing the motor and behavioral symptoms, as well as the neuropathology observed in the brain. RNA interference methods are also being developed by other groups to reduce the huntingtin protein.
Source: American Academy of Neurology