Gene Therapy Increases Survival in Huntington's Disease Animal Models

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. Normal persons have a CAG repeat count of between 7 and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of huntingtin is broken down into toxic peptides, which cause the loss of a type of brain cell called striatopallidal medium spiny projection neurons (MSNs). Destruction of these cells causes involuntary movements, problems with coordination, and, ultimately, in cognitive decline and depression. There is currently no treatment for this fatal disease.

Investigators at the University of Rochester Medical Center (NY, USA) and their colleagues at the University of Iowa (Iowa City, USA) initially worked with a Huntington's disease mouse model. They injected these animals with adeno-associated viruses (AAVs) modified to deliver the genes for the proteins BDNF (brain derived neurotrophic factor) or noggin. BDNF stimulates neural stem cells to produce neurons, while noggin inhibits the molecular pathway that induces formation of glial cells.

Results reported in the June 6, 2013, issue of the journal Cell Stem Cell revealed that a single injection of the adeno-associated viruses AAV4-BDNF and AAV4-noggin triggered the sustained recruitment of new MSNs in wild-type and R6/2 mice, a Huntington's disease model. Mice treated with AAV4-BDNF/noggin or with BDNF and noggin proteins actively recruited progenitor cells to form new MSNs that matured and achieved circuit integration. The AAV4-BDNF/noggin-treated R6/2 mice showed delayed deterioration of motor function and substantially increased survival.

In a follow-up set of experiments, squirrel monkeys that were given injections of adenoviral BDNF/noggin showed similar addition of striatal neurons.

"This study demonstrates the feasibility of a completely new concept to treat Huntington's disease, by recruiting the brain's endogenous neural stem cells to regenerate cells lost to the disease," said senior author Dr. Steve Goldman, professor of neurology at the University of Rochester Medical Center. "The sustained delivery of BDNF and noggin into the adult brain was clearly associated with both increased neurogenesis and delayed disease progression. We believe that our data suggest the feasibility of this process as a viable therapeutic strategy for Huntington's disease."

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University of Rochester Medical Center
University of Iowa