Double gene therapy leads to lasting benefits in SMA mouse model
A combination genetic therapy approach designed to restore more normal activity of the SMN1 gene improved motor function and prolonged survival in a spinal muscular atrophy (SMA) mouse model.
Called Gene-DUET, it involves supplementing the body with additional healthy SMN1 genetic material, an approach similar to the approved gene therapy Zolgensma, along with editing a person’s own genetic code in beneficial ways.
“Our Gene-DUET strategy provides new exploratory avenues for the treatment of SMA in humans,” the researchers wrote in “Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing,” which was published in Nature Communications. “This approach has great potential for the field of genome-editing technologies that may hold potential implications for the treatment of various inherited diseases, particularly neurodegenerative and neuromuscular disorders.”
SMA is caused by mutations in the SMN1 gene, which leads to a lack of the SMN protein needed for the health of nerve cells in the spinal cord, called motor neurons, that coordinate voluntary muscle control.
Zolgensma is designed to provide patients with a new, working version of SMN1. It’s packaged into a viral carrier and given as a single infusion into the bloodstream. While intended as a one-time treatment, it’s not known how long a single infusion’s effects will last and there’s no guarantee the restored SMN1 activity will be permanent.
That’s because, while the supplemented genetic material enters human cells and can produce SMN protein, it doesn’t directly insert itself into the genetic code, meaning its effects could fade over time as the cells it enters are replaced with new ones.
Another possible strategy is gene editing, wherein a person’s DNA is edited to allow production of more SMN protein. This may result in more permanent effects.
Current gene-editing approaches aren’t very good at editing motor neurons, however. That’s in part because these cells are non-dividing, meaning they don’t produce genetically identical copies of themselves to create new motor neurons. As such, they don’t use a type of repair mechanism standard gene-editing techniques usually leverage to take effect.
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Gene editing plus gene supplementation
The study’s scientists recently developed a type of gene-editing strategy called homology-independent targeted integration (HITI) that was designed to help overcome those limitations and allow long-term editing in non-dividing cells. It employs CRISPR-Cas9, a powerful gene-editing technology.
Here, the scientists demonstrated HITI’s potential for correcting genetic defects in mouse spinal cord neurons.
They delivered an SMN1-targeted gene-editing therapy to a mouse model of SMA, showing it led to significantly improved walking capacity, increased body weight, and prolonged survival relative to untreated mice.
Still, the benefits weren’t sustained and the treated mice died very young. The scientists suspected this was related to the fact that even at birth, SMA-affected mice already showed substantial signs of disease that couldn’t be corrected with HITI alone.
They then designed a strategy called Gene-DUET, wherein HITI gene editing was combined with a Zolgensma-like approach where additional healthy SMN1 is also provided.
Both SMN1 supplementation alone and the combined DUET treatment were associated with therapeutic benefits that lasted into adulthood, including increased body weight and motor improvements. They also partially normalized gene activity changes in the spinal cords of the mice, suggesting the treatments “reverse the molecular dysfunction in the spinal cord of SMA mice.”
Survival was improved either way, but DUET-treated SMA mice survived significantly longer than those who only received the gene supplementation approach, indicating gene editing and gene addition offer a “synergistic effect” that maximize benefits, wrote the researchers, who believe the DUET strategy could provide permanent gene correction for treating SMA, but said more work is needed.
A possible consequence of gene therapy is liver or nervous system toxicity. Future studies should explore these possible Gene-DUET side effects in larger animal models before it can be applied in the clinic, researchers said.
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