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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Regenerative gene therapy approach sees success in Huntington’s mouse model

Researchers at the GHM Institute of CNS Regeneration successfully generate new neurons in a mouse model of Huntington’s disease.

Researchers at a neurodegeneration center at Jinan University, China, have developed a gene therapy to generate functional neurons in a mouse model of Huntington’s disease (HD). The treatment resulted in improved motor function in the mice, as well as a significantly extended lifespan.

HD is a rare but devastating condition that can severely curtail quality of life and long-term survival in those affected. An expansion of CAG triplet repeats in the Huntingtin (Htt) gene leads to mutant Htt protein that misfolds and forms aggregates, which in turn leads to loss of brain cells and progressive mental and motor decline.

In this Nature Communications study, researchers focused on GABAergic medium spiny neurons (MSNs), a type of inhibitory neuron which make up more than 95% of the neurons in the striatum region of the brain. MSNs are susceptible to aggregates of mutant Htt and show early degeneration in Huntington’s patients.

Previous work on HD has focused on reducing mutant Htt aggregates via various means, or focused on treating the symptoms. But newer cell conversion technology offers a different approach: regenerating functional neurons in the brain by reprogramming a subtype of glial cells known as cortical astrocytes. Reprogramming the brain’s own cells would also sidestep the issue of possible immunorejection if transplanted foreign cells were used.

Using viral vector-mediated expression of two neural transcription factors known to promote neuronal generation, the team reached an astrocyte-to-neuron conversion rate of 80% in the striatum. The converted neurons were able to fire action potentials and display spontaneous synaptic events, indicating that they are behaving as functional neurons. Perhaps even more promisingly, the treated mice displayed longer lifespans and improved motor function over their untreated counterparts.

The study authors are hopeful that these results could eventually lead to disease-modifying therapies for both HD and other neurodegenerative diseases.

Dr Gong Chen, lead author, commented: “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 HD patients. Obviously, reducing mHtt aggregates at [an] early stage might slowdown the disease progression but it cannot regenerate new neurons for the late stage patients. An ideal approach may be to combine our neuroregenerative approach together with gene correction technology to generate healthy new neurons in future studies.”

Source: Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease. Wu Z et al., Nature Communications, February 2020. DOI

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