A protein that can specifically bind to mutated forms of huntingtin and prevent its production — while preserving the normal versions of this protein — may represent a new strategy to attack Huntington’s disease.
Researchers from Sangamo and Shire are going to present results from preclinical studies of this potential treatment approach in mouse models of Huntington’s at the upcoming 22nd Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT).
The oral presentation, “Repression of mHTT Expression in Huntington’s Disease Mouse Models by AAV-Mediated Expression of Zinc-Finger Protein-Repressor Transgene,” will take place April 29 in Washington, D.C. (Editor’s note: See page 34 of document.)
Huntington’s is a neurodegenerative disease caused by the expansion of a small stretch of DNA, called a CAG trinucleotide repeat, in the HTT gene. Addition of these CAG repeats leads to the production of a mutated version of the huntingtin protein, which forms toxic clumps that prevent the normal function of nerve cells.
These expanded CAG repeats are thought to form an anchorage site for other proteins to bind, resulting in aggregates that lead to the disruption of normal cellular functions.
Finding ways to prevent the production of mutated huntingtin (mHTT) protein, but still preserve its natural, healthy version, holds potential as a treatment strategy for Huntington’s disease.
They screened more than 1,600 zinc-finger proteins (ZFP), which can recognize and bind to small DNA sequences, that had been fused to a repressor domain. These were then tested in Huntington’s patients’ cells and in stem cell-derived neurons.
The team identified specific ZFPs that could promote a 90% reduction in mHTT levels with no effect on the amount of healthy HTT protein available. Further analysis showed that the lead repressive ZFP had very limited off-target (unspecific) effects in human cells, suggesting it is highly selective for the mutant form of the huntingtin protein.
Researchers then used an adeno-associated viral vector (AAV, commonly used in gene therapies) to deliver ZFPs into the brains of two mouse models of Huntington’s disease.
Their lead repressive ZFP could significantly reduce, in a dose-dependent manner, brain levels of mHTT. These effects were sustained in multiple brain regions for up to 33 weeks after administration.
Importantly, these positive effects were accompanied by improvement in motor function, as determined by the mice’s ability to walk and maintain balance.
“Based on these encouraging results, we will execute investigational new drug (IND)-enabling studies to evaluate this potential clinical candidate for the treatment of Huntington’s disease,” researchers wrote.