"This platform avoids the liver, allowing therapies to more effectively target areas such as the brain and lungs. It is less toxic than current delivery platforms, while also avoiding stimulating the immune system. This means it allows for repeat dosing, which is crucial in addressing diseases requiring ongoing or multiple interventions.
To demonstrate that the new platform could deliver the genetic payload without being intercepted by the liver, Lewis’ team created a gene therapy using a protein that aids in muscle development, often associated with a particularly muscular breed of cattle known as Belgian Blues. When introduced into mice, the platform not only evaded the liver but resulted in genetically modified mice with twice as much muscle mass as their untreated counterparts. "
If it does not work with us, we will at least have huge rats!
Written by
Maxone73
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Good find, Max. Here are some interesting comments from the end of the full report:
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While promising results have been obtained with AAV vectors, their small cargo capacity and anti-AAV immune responses limit their use.9,81,82,83 The large cargo capacity of FAST-PLVs indicate potential for the development of CRISPR-Cas9 gene editing technologies.83,84 Successful gene editing requires delivery of both Cas9 protein and a guide RNA (gRNA) to the target cell. Cas9 transgenes are approximately 4.2 kb, which puts them at the upper end of AAV packing capacity.85 Utilizing FAST-PLVs would enable both Cas9 and gRNA sequences to be included on a single pDNA. Alternatively, Cas9 and gRNA could be co-encapsulated into the same PLV, which would enable the use of either pDNA or mRNA or a combination of both.
In summary, we present an approach to achieve systemic nucleic acid delivery by combining the fusion-inducing activities of FAST proteins with the improved safety and scalability of lipid-based non-viral delivery vectors. Given the small size of FAST-PLVs, as well as their efficacy, low immunogenicity, high tolerability, and the ability to reach extrahepatic tissues, we anticipate that FAST-PLVs will have substantial clinical utility, enabling the development of low-cost genetic medicines in the near future.
Limitations of the study
In this study, we demonstrate delivery of mRNA and pDNA by using the FAST-PLV platform and several routes of administration, resulting in expression in a wide range of tissues. A thorough investigation of cell types transfected in animal models was not conducted. Knowledge of cell tropism will provide additional insight into suitable therapeutic targets and potential indications. For example, in the lung, robust delivery to basal and/or club cells would allow for the treatment of cystic fibrosis,101 while delivery and expression in T cells would enable the development of chimeric antigen receptor T cell therapies. Additionally, we did not examine the delivery of genome editing cargoes, which have the potential to revolutionize treatment for many devastating genetic diseases. We also did not extensively assess long-term expression kinetics for therapeutic pDNA cargoes. While we demonstrate here the expression of a reporter (pDNA-FLuc) for up to 1 year, we found that the kinetics of expressed FST were substantially different than those of a reporter, for example. A comprehensive understanding of the mechanisms regulating therapeutic gene expression will vastly improve treatment strategies moving forward. (Emphasis added)
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The detailed full report can be found here:
Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles, Cell, Article, Volume 187, Issue 19p5357-5375.e, 24September 19, 2024:
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