Scientists have drawn closer to the first treatment for Huntington’s disease (HD), demonstrating the effectiveness of a molecule that targets disease-causing mutant proteins while preserving those that function normally.
The molecule, called zinc finger protein transcriptions factor (ZFP-TF), repressed a significant portion of the mutant protein in patient-derived neurons, and long-term functional improvement was seen among mice with a model of Huntington’s disease, according to the study published in Nature Medicine.
D. James Surmeier, PhD, chair and Nathan Smith Davis Professor of Physiology, and Michelle Day, PhD, and Jyothisri Kondapalli, PhD, both research associate professors of Physiology, were co-authors of the study.
Huntington’s is a degenerative disease characterized by progressive motor and cognitive impairment, caused by a buildup of toxic proteins in neurons. This toxic protein buildup is triggered by an inherited mutation in a single gene, the Huntington gene (HTT).
Normally, this gene provides instructions for making a protein called huntington. While the exact function of this protein is unknown, it is essential for normal development, according to previous studies. However, in Huntington’s disease, the inherited mutation expands the size of the gene, producing an abnormally long protein that falls apart before binding together and thus accumulating in neuron cells.
While certain treatments or physical therapy can help patients manage symptoms, there is currently no disease-modifying therapy for Huntington’s disease.
Because normal HTT is needed in the brain, scientists were searching for a molecule that could reduce the amount of mutant HTT (mHTT) while leaving normal HTT untouched. Previous attempts have explored using transcriptional inhibitors that would selectively lower mHTT, but those studies have yielded only modest reduction in the mutant protein.
Instead, the current study used ZFP-TF, which directly targets the area of the gene expanded through mutation. The scientists tested this molecule in neurons derived from patients with HD, delivering the molecule piggybacked on a harmless virus that infects cells and can alter their genome. After injecting cells with this virus, the study found that ZFP-TF repressed more than 99 percent of mHTT genes, while 86 percent of normal HTT genes were left alone.
This translated to functional improvement: mice modeling HD and treated with ZFP-TF performed much better on physical tests when compared to control mice who received no treatment. When the authors examined the treated mice’s brains, they found a 62 percent reduction in mHTT proteins and little evidence of neurodegeneration.
MRI-guided delivery of altered viruses for gene therapy is already being used to treat a variety of conditions in human patients, and while the treatment molecule itself needs further refinement, this study shows that a one-time injection of ZFP-TF has the potential to someday treat Huntington’s disease, according to the authors.
This work was jointly supported by Sangamo Therapeutics and the CHDI Foundation, and some of the other study authors are current or former employees of Sangamo Therapeutics.