The inspiring potential of gene therapy in neurology

September 7, 2022 Article BioVox

Dr. Monica Bennett is Head of Gene Therapy Unit at Novartis, the company behind the world’s only gene therapy approved for a neurological indication. Zolgensma treats children with spinal muscular atrophy (SMA), a genetic condition where infants with the most severe type rarely survive past their first few years of life. We spoke to Dr. Bennett about her experience working with SMA kids and their families, and the inspiring potential of gene therapy in other neurological diseases.

This article by Amy LeBlanc is part of a series on gene therapy in the lead up to Science for health 2022, where Dr. Monica Bennett will give a talk on AAV gene therapies for neurological disorders.

Q: How did you get involved in gene therapy and what do you love most about working in this field?

Monica Bennett: “As a postdoc at Harvard I was screening for small molecules in SMA, and I would meet with families where one or more of their children were patients. In the more severe cases, these young kids would be on respirators, have gastrostomy tubes, and be completely unable to move around. Their parents would ask us: ‘when do you think there will be a treatment?’. But at that time, there was really nothing available, and we would have to deliver that devastating news.

“At my last company I was also working on SMA. While there, the first truly disease-modifying SMA treatment was approved: SPINRAZA, an antisense oligonucleotide. And it was transformative – certainly much better than the steroids we’d been using until then – but it still didn’t lead to a complete reversal of the disease.

“You see the impact of these gene therapy treatments not only on the children, but their families too. So many lives are affected – it’s really just miraculous.” – Monica Bennett

“Then one day I went to a conference where AveXis [later acquired by Novartis] was showing results from the early clinical trials of the gene therapy Zolgensma. I remember just being in awe. I was so impressed by the data – there had never been such an effective treatment . It radically changed patient lives. Then and there, I knew I wanted to work in gene therapy, and less than a year later I joined Novartis.

“I love my job – working in gene therapy is the coolest job I’ve ever had. Now, I get to meet families where their 5-year-old son is running up and down our suite. A boy who, had he not been treated, wouldn’t have been alive today. And you see the impact of these gene therapy treatments not only on the children, but their families too. So many lives are affected – it’s really just miraculous.”

Q: What currently happening in the neuro gene therapy landscape?

Monica Bennett: “So far, Zolgensma is the only gene therapy approved by the EMA and FDA in a neurological indication. But the approval of this therapy has really opened up a world of possibilities for other hard-to-treat diseases. Because it is difficult to deliver therapies to the brain, but the vector used in Zolgensma – adeno-associated virus 9 (AAV9) – is very good at crossing the blood-brain barrier. So now we have this whole new treatment modality where – as long as you know what gene you want to deliver – there is a potential avenue forward towards a cure.

For more on the past and future of the field, read this interview with gene therapy pioneer Dr. Katherine High!

“There are now a few potential gene therapies for neuro indications in clinical trials. They are mostly AAV-based gene therapies, but there are also some in the siRNA space. Trials have primarily centered on monogenetic neurodevelopmental disorders with young patient populations (like SMA). But we are starting to see a broadening into other indications, including neurodegenerative diseases like ALS, Parkinson’s and even Alzheimer’s.

Q: What are you most excited to see in the future?

Monica Bennett: “The next wave of progress is still in the preclinical phase, which is what I like to think of as ‘innovative technology payloads’. If AAV vectors are the vehicles that get you on site, then the payloads are the workers piling out of the cars to fix the genetic issue. One of the limitations of AAV is that you can only fit so much in the vehicle; your payload can only be up to a certain size. This becomes an issue for gene replacement in diseases like Duchenne muscular dystrophy, where the gene you want to deliver is simply too big. To some degree, you can clip the gene into smaller mini-genes, but this method comes with a slew of additional challenges.

“The next generation of AAV gene therapies are going to involve exciting new payload technologies and reengineered capsids. It’s the future I see for gene therapy: innovative and inspiring.” – Monica Bennett

“To overcome the size limitation of AAVs, people are currently hard at word developing the next generation of payload technology: things like CRISPR and zinc fingers. I’m particularly excited about zinc fingers, which are elements that bind to DNA, where they have different effects depending on how you engineer them. Traditionally, they’ve primarily been used to repress gene expression. But at Novartis we’re currently collaborating with a company called Sangamo Therapeutics, which has created zinc fingers that can be used to instead activate gene expression. This means we can potentially use them to treat diseases caused by haploinsufficiency, where patients have one good and one bad copy of a gene. The zinc fingers can, in theory, simply augment the expression of a person’s one good gene to compensate for the defective one and reverse the disease pathology. And they’re very small, which means they’re easy to pack into an AAV capsid for delivery!

“I think we’re still in the early stages of gene therapy in neurology. Although some of the low hanging fruit is now gone, the next generation of AAV gene therapies are going to involve exciting new payload technologies and reengineered capsids. It’s the future I see for gene therapy: innovative and inspiring.”

Interested in the topic of gene therapy? Then join Dr. Monica Bennett in attending Science for health on 21 November 2022, in Brussels or online!


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