First Clinical Trial of a Genetic Therapy for Huntington’s Disease Nears Completion
Wave Life Sciences also has created an antisense oligonucleotide for Huntington’s disease that is in the late preclinical stages of development. The company uses a type of chemistry that allows it to control the stereoisomer composition of the nucleic acids. The therapy targets specific single-nucleotide polymorphisms on mutant huntingtin and therefore may not be appropriate for every patient with Huntington’s disease. “This [treatment] has at least the potential for allele-specific targeting … and will hopefully be entering the clinic fairly soon,” said Dr. Leavitt.
Other gene-therapy approaches require a vector, most often a nonpathogenic adeno-associated virus (AAV), to bring the treatment into the CNS. Several such therapeutic candidates in preclinical development are close to entering early human trials, said Dr. Leavitt.
UniQure is developing a form of AAV5 that expresses an artificial micro-RNA that targets huntingtin. The drug will require stereotaxic injection directly into the brain. In one study, direct intraparenchymal injection of the drug significantly reduced levels of mutant huntingtin in the putamen, caudate, and thalamus of a minipig model of Huntington’s disease. The drug had less effect in the cortex. Depending on where the virus is injected, viral approaches generally have good local targeting, but not necessarily widespread targeting, said Dr. Leavitt. Spark Therapeutics and Voyager Therapeutics are also developing therapies similar to that of UniQure.
—Erik Greb
Suggested Reading
Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012; 74(6): 1031–1044.
Southwell AL, Smith SE, Davis TR, et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 2015;5:12166.
Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015;125(5):1979-1986.
