Gene Therapy Approach Reported to Block Mutant Huntington’s Gene in Preclinical Studies

uniQure recently published results from preclinical studies of its gene therapy program, AMT-130, indicating that a one-time administration of AAV5-delivered therapy into the central nervous system can block the mutant HTT gene that causes Huntington’s disease (HD).

These findings, in the article “Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington’s Disease,” were published in the  Molecular Therapy-Nucleic Acids journal. The data also formed the basis of a presentation for the 11^th Annual CHDI Huntington’s Disease Therapeutics Conference that took place on Feb. 24, 2016, in Palm Springs, California.

Huntington’s disease is a neurodegenerative disorder that reduces muscle coordination and leads to behavioral and cognitive decline over time. Though the causes of HD are still not fully understood, a number of studies have shown that genetic mutations leading to the formation of an altered form of a protein called mutant Huntingtin (HTT) leads to HD development.

From the therapeutic standpoint, no cure has yet been developed for HD, and uniQure’s published preclinical results describe multiple promising approaches to block the mutant HTT gene using a concept based on the expression of cassette-optimized artificial microRNAs (miHTTs).

A number of miHTT scaffolds were integrated within an AAV5 vector using uniQure’s baculovirus-based manufacturing platform. These vectors were then administered to humanized mouse models.

Findings demonstrated strong silencing of mutant HTT, and total HTT silencing both in vitro and in vivo, the company announced in a press release. Efficient blocking of the mutant HTT gene also could reach up to 80 percent when optimized miHTT scaffolds were employed.

“Huntington’s disease devastates families and there is currently no effective disease-modifying treatment,” Charles W. Richard, MD, PhD, senior vice president, Research and Development, Neuroscience at uniQure, said in the release. “We are excited by the results of this study, and believe this degree of knock-down of mutant Huntingtin protein, if duplicated in our ongoing non-human primate safety toxicology studies and future human clinical trials, could significantly alter the course of the disease.”

Currently, uniQure is pursuing studies on AMT-130 to support the investigative new drug application it plans to file with the U.S. Food and Drug Administration (FDA).

“Dr. [Pavlina] Konstantinova and her team have made significant progress in the search for an effective treatment for this cruel neurodegnerative disorder,” said Dan Soland, chief executive officer of uniQure. “AMT-130 now represents our third gene therapy product candidate in the CNS [central nervous system] area … We will continue to leverage our deep experience in the CNS field, as well as our validated manufacturing capabilities and AAV5 technology, to advance AMT-130 towards the clinic.”