First Clinical Trial of a Genetic Therapy for Huntington’s Disease Nears Completion
VANCOUVER—Antisense oligonucleotides hold promise as treatments for Huntington’s disease, according to an overview delivered at the 21st International Congress of Parkinson’s Disease and Movement Disorders. Preclinical evidence suggests that these treatments are safe and will decrease levels of mutant huntingtin in the brain. The first clinical trial of an antisense oligonucleotide for Huntington’s disease is currently under way and fully enrolled. Results will be available in the near future, said Blair R. Leavitt, MDCM, Professor of Medical Genetics at the University of British Columbia in Vancouver.
What Are Antisense Oligonucleotides?
Antisense oligonucleotides are small, artificial units of DNA that are modified chemically to have a long half-life. They can be targeted to bind to any RNA in the body, and when they bind with huntingtin messenger RNA, they prevent production of mutant huntingtin protein. In theory, this action should prevent all subsequent pathology and delay or prevent the onset of Huntington’s disease, said Dr. Leavitt.
Among the advantages of antisense oligonucleotides is that neurons and glia take them up freely. They reach the desired areas of the brain without requiring a vector to introduce them. Antisense oligonucleotides are stable, have a long term of activity, act in a dose-dependent manner, and have reversible effects. “They are much like our classic small-molecule drugs, so we are comfortable bringing these therapies into clinical development,” said Dr. Leavitt.
Preclinical Data Indicate Safety
Kordasiewicz and colleagues infused 75 mg of an antisense oligonucleotide directly into the brain of a mouse model of Huntington’s disease (ie, BACHD mice) over 14 days. They observed a decline in huntingtin RNA that endured for as long as three months. The treated mice had better motor coordination and performed better on the rotorod test. The treatment also slowed the loss of brain mass and improved hypoactivity and anxiety.
The investigators also showed that antisense oligonucleotide reached the brain after intrathecal administration to monkeys. The treatment reduced huntingtin levels by approximately 50% in the cortex, and by between 20% and 25% in deep brain structures.
A Potential Biomarker of Target Engagement
To gauge treatment efficacy in humans, neurologists need a noninvasive way to measure levels of huntingtin in the brain. It is not yet possible to measure brain huntingtin levels directly using imaging, but CSF levels of huntingtin could be a surrogate measure, Dr. Leavitt said.
Dr. Leavitt and colleagues developed an ultrasensitive single-molecule counting immunoassay that successfully quantified mutant huntingtin in the CSF of patients with Huntington’s disease. Mutant huntingtin was undetectable in healthy controls. Patients with manifest Huntington’s disease had three times more mutant huntingtin than asymptomatic mutation carriers did. Huntingtin levels increased as the disease progressed. In addition, huntingtin concentration predicted cognitive and motor dysfunction.
The investigators observed similar findings after they used microbead-based immunoprecipitation and flow cytometry to develop a second highly sensitive assay for detecting mutant huntingtin. They demonstrated that CSF levels of mutant huntingtin reflect brain levels of the protein in mouse models of Huntington’s disease, and in patients with Huntington’s disease, the levels increased with disease stage. They also demonstrated that CSF huntingtin levels decreased following suppression of huntingtin in the brain.
A Clinical Trial Nears Completion
Ionis Pharmaceuticals developed an antisense oligonucleotide that targets both the mutant and normal alleles of huntingtin. Investigators subsequently began a first-in-human phase I/IIa trial of the drug in patients with early Huntington’s disease. Participants were randomized 3:1 to drug or placebo at sites in the United Kingdom, Germany, and Canada. The drug is administered intrathecally, and maximal protein suppression occurs approximately four weeks later. Each study participant will undergo intrathecal injections every month for four months.
The trial’s primary objective is to evaluate the treatment’s safety and tolerability. Its secondary objective is to examine the drug’s CSF pharmacokinetics. Finally, an exploratory objective is to assess the treatment’s effect on pharmacodynamic biomarkers and on clinical end points of Huntington’s disease.
All of the participants have been enrolled in the study, and Dr. Leavitt administered an intrathecal infusion to the first subject at the Vancouver site in September 2015. Participants are generally in good health and have high levels of function. Thus far, the researchers have found no evidence of significant adverse events or safety concerns, and the drug appears tolerable, said Dr. Leavitt. Results of the trial should be available in the coming months, he added. “This is certainly exciting, and it is the first time we have been able to bring a genetic therapy into the clinic for this devastating disorder.”
