Newly Discovered Structure Could Boost Gene Therapy Efficacy


Certain amino acids may be key to delivering effective, low-dose gene therapy for neurologic conditions.

Gene therapy is a groundbreaking advancement that has the potential to transform treatments and provide cures for serious diseases, including neurological conditions. However, due to the viral component of gene therapy for these conditions, adverse events may occur with high doses, which poses a challenge for treatment.

A novel structure of viruses that deliver the therapeutic gene may help them better cross the blood-brain barrier, a crucial component of administering lower-dose gene therapies for brain and spinal conditions, according to a study published by Molecular Therapy.

Related Coverage: The Past and Future of Gene Therapy

“This structural ‘footprint’ we found seems to help these viruses get efficiently into the brain, which informs the design of potentially safer brain-targeted gene therapies,” said study senior author Aravind Asokan, PhD.

Adeno-associated viruses (AAVs) are commonly used for delivering gene therapies. Naturally-occurring AAVs typically infect individuals without causing disease. In terms of gene therapy, researchers remove most of the AAV genome, replace it with therapeutic substances, and inject trillions into the patient, according to the study.

Most AAVs are unable to easily migrate from the bloodstream to the brain due to the tightly-lined brain capillaries that form the barrier, according to the authors.

“To achieve therapeutic effects in the brain, AAVs sometimes have to be given in high doses, which raises the possibility of dose-dependent toxicity,” said first author Blake Albright.

In the study, the researchers isolated features that allow AAVs to easily cross the blood-brain barrier by comparing a virus that crosses the barrier to a virus that does not. The authors developed a small library of novel AAV variants by swapping their DNA.

The new AAVs were then tested in mice. The results showed the researchers were able to isolate a set of 8 amino acids that boost the ability to cross the barrier, according to the study.

“Grafting that structural footprint onto another AAV strain enables it to cross into the brain much more easily,” Albright said.

This finding suggests that the addition of these 8—or a similar set of amino acids—may help AAVs for gene therapies that target the brain or spinal cord to improve drug delivery, according to the study.

Since the gene therapy is more effective, it could also be administered in smaller doses and reduce the risk of adverse events.

Another potential safety benefit was that AAV variants were less likely to enter non-brain cells, especially liver cells, according to the study. The authors noted that liver toxicity is a large concern for high-dose gene therapy.

These findings may be useful for several gene therapies currently in the pipeline for amyotrophic lateral sclerosis, Huntington’s disease, spinal muscular atrophy, Friedrich’s ataxia, and other neurological diseases, according to the study.

“We also found that our AAV variants containing this key amino acid footprint preferentially get into neurons rather than other brain cell types,” Dr Asokan said. “This could be particularly useful for some gene therapies that target the brain.”

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