Novel Gene Therapy Generated New Functional Neurons in Mouse Models of Huntington's Disease (HD)

Nature Communications Publication Demonstrates Proof of Principle for Neuroregenerative Approach Pioneered by Founder and Chief Scientific Officer of NeuExcell Therapeutics

Researchers See Potential Therapeutic Applications in HD and Other Serious Disorders of the Central Nervous System

March 12, 2020 03:00 PM Eastern Daylight Time

STATE COLLEGE, Penn.--(BUSINESS WIRE)--NeuExcell Therapeutics, Inc., an early-stage gene therapy company focusing on neurodegenerative diseases, today announced the publication of research demonstrating proof of principle for the company’s investigational gene therapy, which generated functional new neurons in animal models of Huntington’s disease (HD). The results, published in the current issue of Nature Communications1, show that the new gene therapy led to improvement in HD symptoms and extension of lifespan in validated mouse models, indicating a promising approach to treating this disease and other serious central nervous system (CNS) disorders.

“They can project their nerve fibers 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.”

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The Nature Communications paper describes how a research team led by Gong Chen, PhD, NeuExcell’s founder and chief scientific officer, developed an adeno-associated virus-based (AAV-based) gene therapy to regenerate functional new neurons in the brains of mice with HD-like symptoms. The mice treated with this gene therapy exhibited improved motor skills and an increased rate of survival compared to untreated mice.

Dr. Chen, a former professor at Penn State University and now leading a brain repair center at Jinan University in China, pioneered this gene therapy approach to neuroregeneration, which delivers specific neural transcription factors to a targeted site in the brain or spinal cord. The transcription factors can reprogram cells of the appropriate lineage that are already present in the damaged region to produce functional new neurons and repair damaged brain tissue.

“The newly generated neurons work like preexisting mature neurons,” said Dr. Chen. “They can project their nerve fibers 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 novel gene therapy works by converting astrocytes in the CNS into functioning neurons.2-5 Astrocytes are a type of glial cells that are present throughout the CNS and are more abundant than neurons. Introducing neural transcription factors NeuroD1 and Dlx2 into astrocytes in the striatum of HD mice allows for the generation of GABAergic neurons, resulting in increased motor function and improved quality and length of life.

GABAergic medium spiny neurons (MSNs) comprise roughly 95% of total neurons within the striatum region of the brain, and they are susceptible to mutant huntingtin protein aggregates, which are associated with early striatal degeneration in patients with HD. Many symptoms observed in patients with HD are related to loss of MSNs in the striatum. Dr. Chen and colleagues reported that the gene therapy converted 80% of viral infected astrocytes in the striatum into functional GABAergic neurons, and 60% of the newly generated neurons were the right type of MSNs. “Such high neuroregeneration 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 HD mice,” Dr. Chen noted.

Every single neuron in the brain is surrounded by supporting glial cells. As a result, such direct glia-to-neuron conversion technology offers great advantages over other therapies such as stem cell transplantation therapy. Unlike external stem cell transplantation, NeuExcell’s innovative gene therapy produces newly generated neurons using internal glial cells, eliminating the risk of rejection by the body’s immune system.

“It’s exciting for the neurology community to see important work being done to advance this novel gene therapy technology,” said Pedro Gonzalez-Alegre, MD, PhD, associate professor of neurology and director of the Huntington Disease Center of Excellence at The University of Pennsylvania. “Although the research is still in its early stages, the potential of this therapy in a progressive condition like Huntington’s disease offers hope for patients looking for a better quality of life.”

In addition to the successful conversion of astrocytes to neurons and the resulting improvement in HD symptoms, Dr. Chen sees this type of neuroregenerative gene therapy as potentially beneficial in other neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and ALS (amyotrophic lateral sclerosis), as well as in cases of ischemic cortical stroke, traumatic brain or spinal injury.

About Huntington’s Disease
Huntington’s disease is a fatal, progressive neurological condition that usually strikes adults in their thirties or forties. The hallmark symptoms of HD are uncontrolled movements and difficulty in walking, speaking, and swallowing. Other symptoms include changes in personality and difficulty with thinking, comprehension, and memory.

HD is a genetic disease. The HTT gene creates a protein called huntingtin, which is thought to play an essential role in brain function. A mutation in the HTT gene results in faulty huntingtin proteins, negatively affecting brain function.

About NeuExcell Therapeutics, Inc.
NeuExcell Therapeutics, Inc. is a preclinical gene therapy company based in State College, Pennsylvania, focusing on neurodegenerative diseases. NeuExcell developed a disruptive neuroregenerative gene therapy that utilizes in vivo astrocyte-to-neuron conversion technology for brain repair. While potentially applicable to many conditions including Alzheimer's, Parkinson's, ALS, traumatic brain injury, and spinal cord injury, NeuExcell is currently focusing on two leading preclinical programs of Huntington's disease and ischemic cortical stroke, where the company has very robust preclinical data (including non-human primate data) and a clear path forward. The company’s vision is to improve the quality of life for millions of patients worldwide who are suffering from neurodegenerative conditions by using the power of gene therapy to restore damaged neural tissue.


Wu Z, Parry M, Hou XY, et al. Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease. Nat Commun. 2020;11(1):1105.


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Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 2014;14(2):188-202.


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Chen YC, Ma NX, Pei ZF, et al. A NeuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Mol Ther. 2019;28(1):217-234.
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Zhang L, Lei Z, Guo Z, et al. Reversing glial scar back to neural tissue through NeuroD1-mediated astrocyte-to-neuron conversion. BioRxiv. 2018. doi:
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Ge LJ, Yang FH, Feng J, et al. In vivo neuroregeneration to treat ischemic stroke in adult non-human primate brains through NeuroD1 AAV-based gene therapy. BioRxiv. 2019. doi:
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