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New Gene Therapy for Huntington’s Disease Proves Successful in Mice

A novel gene therapy that reprograms glial cells into neurons extends life span of mice with Huntington’s disease.

Huntington’s disease is a fatal degenerative brain disorder caused by mutations in the Huntington gene. This creates faulty proteins that result in degradation of GABAergic neurons, which comprise 95 percent of all neurons within the striatum of the brain.

In a paper published in Nature Communications, NeuExcell Therapeutics Inc., an early-stage gene therapy company focusing on neurodegenerative diseases, describes a novel gene therapy that can directly convert striatal glial cells – the most abundant cell type in adult mammalian brains – into functional GABAergic neurons in mice afflicted with Huntington’s.

The in vivo approach works by delivering neural transcription factors NeuroD1 and Dlx2 to striatal glial cells already present in the damaged region. The transcription factors then reprogram them to convert into GABAergic neurons and repair damaged brain tissue.

“Because every single neuron in our brain is surrounded by supporting glial cells, such direct glia-to-neuron conversion technology offers great advantages over stem cell transplantation therapy in terms of high efficiency of neuro-regeneration and no worries about immuno-rejection,” said Gong Chen, lead author as well as NeuExcell’s founder and chief scientific officer.

Chen, also a former professor at Penn State University and now leading a brain repair centre at Jinan University in China, reported that the gene therapy converted 80 percent of infected striatal glial cells into functional neurons, and 60 percent were of the right GABAergic type.

“Such high neuro-regeneration efficiency explains the significant motor functional recovery after our gene therapy treatment and even more strikingly, a significant extension of life span among the treated mice,” Chen noted.

The authors further observed that the new neurons were electro-physiologically functional, forming synaptic connections with other neurons. They could also project their axons to the right target areas, suggesting that they have integrated into global brain circuits.

“The newly generated neurons work like pre-existing mature neurons,” said Chen. “They can project their nerve fibres to the right target areas of the brain and make functional connections with other neurons. Essentially, this novel gene therapy produces the right type of neurons in the right place to perform the proper functions.”

The scientists also highlighted that their gene therapy used adeno-associated virus vectors to deliver the transcription factors. “Importantly, here we used the adeno-associated virus vectors, which have been approved by FDA as a common gene therapy vector in many clinical trials, ” said first author Zheng Wu.

“Our regenerative gene therapy approach is different from conventional gene therapy that typically aims at the mutant genes by either correcting the gene mutations or reducing the mutant gene product, such as reducing mHtt aggregates in patients,” added Chen. “Obviously, reducing mHtt aggregates at early stage might slowdown the disease progression but it cannot regenerate new neurons for the late stage patients.” [APBN]