Could gene therapy be used to replace neurons lost to Huntington’s disease?

Written by Alice Bough (Future Science Group)

Researchers from Jinan University (Guangzhou, China) and Pennsylvania State University (PA, USA) have collaborated on a study utilizing gene therapy to reprogram striatal astrocytes into GABAergic neurons. Their approach improved motor function in a mouse model of Huntington’s disease (HD).

The authors of the paper, published in Nature Communications, suggest that this astrocyte-to-neuron conversion approach could be utilized as a new therapy for treating HD and other neurodegenerative disorders.

“We are developing a series of NeuroD1-based gene therapies to reprogram brain internal glial cells directly into functional new neurons to treat a variety of brain disorders including HD, Alzheimer’s disease, stroke, ALS and many more,” commented senior author of the study, Gong Chen (Jinan University).

The group’s approach involved adeno-associated virus-based gene therapy, through which the neural transcription factors NeuroD1 and Dlx2 were expressed in striatal astrocytes.

“In order to generate GABAergic neurons, we combined NeuroD1 together with another transcription factor Dlx2, which is known to generate GABAergic neurons during early brain development, and successfully converted striatal astrocytes into GABAergic neurons in HD mice,” explained first author of the paper, Zheng Wu (Pennsylvania State University).

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Through brain slice recordings, the researchers identified that the new GABAergic neurons were electrophysiologically functional and formed circuits with other neurons, possibly integrating with global brain circuits.

Behavioral tests were performed to analyze changes in phenotype. These revealed that motor function was significantly improved in the treated mice, and further, their lifespan was extended.

“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 mutant Htt aggregates in HD patients,” stated Chen. “Obviously, reducing mutant Htt aggregates at early stage might slowdown the disease progression but it cannot regenerate new neurons for the late stage patients.”

Unfortunately, this gene-therapy approach does not guarantee that the newly generated neurons are protected from mutant Htt. However, the authors hope that utilizing a combination of neuroregenerative gene-therapy and gene-correction technology in future studies will allow them to overcome this issue.

Sources: 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. Comm. 11, 1105 (2020);