I’m a physician scientist, so I run a lab. And we’re involved in developing gene therapy approaches for ALS. So I’m very immersed in this world. The gene therapy as an approach for ALS, the power of that strategy is the ability to reach the relevant cells in the nervous system that need to receive a therapeutic so I personally work with adeno-associated viruses or AAVs to deliver therapeutics that can reach the affected motor neurons in the brain, brainstem, and spinal cord and other groups are achieving that through different strategies like antisense oligonucleotides and people are working on lipid nanoparticles and other delivery methods...
I’m a physician scientist, so I run a lab. And we’re involved in developing gene therapy approaches for ALS. So I’m very immersed in this world. The gene therapy as an approach for ALS, the power of that strategy is the ability to reach the relevant cells in the nervous system that need to receive a therapeutic so I personally work with adeno-associated viruses or AAVs to deliver therapeutics that can reach the affected motor neurons in the brain, brainstem, and spinal cord and other groups are achieving that through different strategies like antisense oligonucleotides and people are working on lipid nanoparticles and other delivery methods. In terms of what is the therapeutic being delivered, there’s a lot of different approaches. So a lot of gene therapy targets a genetic mutation. So if people have a variant in a gene that’s associated with ALS, you could deliver machinery to edit that gene or to deliver a working copy of that gene or to knock down that gene depending on what problem that gene is causing. Additionally, there are some shared downstream things like TDP pathology that can be modulated so what my lab works on is targeting that downstream pathology in our case by a reduction of Ataxin-2 but there are other approaches that we’re investigating and undertaking to unclump TDP-43 and restore it to its nuclear location where it can do its proper functions. So there’s all kinds of different ways that gene therapies are being employed in ALS. So the strategy that’s probably the furthest along clinically is antisense oligonucleotide therapy. So these are stretches of nucleotides that are designed to pair up with DNA or RNA in a cell and modulate its function. So ASOs can knock something down, it can target an RNA for degradation, or it can mediate alternative splicing and correct the function of something. And so one of the therapies that is actually FDA approved is an antisense oligonucleotide that targets SOD1. SOD1 variants are associated with about 2% of all ALS. And for those patients with that disorder, receiving monthly intrathecal injections of tofersen, an SOD1 targeting ASO, extends lifespan significantly. It slows down the disease progression. And now the long-term data is suggesting that about a quarter of patients on that drug stop progressing. And a handful of patients have even shown improvement. So that really shows the power of a gene therapy approach if you are able to target the pathology effectively. There are a lot of therapies in clinical trial right now that are gene therapy-based and that are targeting individual genetic causes or targeting the more general broad pathology in ALS. As I mentioned, when TDP43 is not doing its job in the nucleus, a lot of things are spliced incorrectly, and you can actually lose certain proteins that your cell is meant to have. And so some of those proteins are STABMIN2, UNC13A, and others, and there are gene therapy trials aimed at restoring those, delivering working copies of those genes to offset the pathology seen in ALS.
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