Posted on 4 March 2021
Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.
Why is this research important: Often described as ‘molecular scissors’, the CRISPR Cas9 gene editing system allows us to cut out and, if necessary, replace specific DNA sequences within the cells of living organisms. This offers the potential to permanently cure diseases caused by genetic mutations. One of the main challenges to this application of CRISPR gene editing is the safe and specific delivery of the treatment to the organs and cells that need it. One strategy for delivering CRISPR components is to encapsulate them in particles made of lipids (fat molecules). These lipid nanoparticles can be thousands of times smaller than a red blood cell, and are able to cross cell membranes, after which they dissolve and release their contents.
What did the researchers do: In this study, researchers produced a new type of lipid nanoparticle. They found that by fine-tuning the precise ratio of lipid components, they could design a nanoparticle to specifically target the liver. They then used this nanoparticle in mice to deliver mRNA coding for CRISPR components that would knock down a gene that codes for angiopoietin-like 3 (Angptl3), a protein that inhibits the breakdown of cholesterol by lipases in the liver.
Key takeaway(s) from this research: The new nanoparticles were able to deliver the treatment safely and specifically to the liver, resulting in a reduction in low density lipoprotein (LDL) of 57% and a reduction in triglyceride levels of 29%. These changes were dose dependent, and persisted for several months following treatment. Comparatively, the existing FDA- approved ‘gold standard’ lipid nanoparticles only achieved around a 16% reduction in LDL and triglycerides when used to deliver the same treatment.
Some people carry natural loss-of-function mutations in their Angptl3 gene. This results in reduced levels of LDL and triglycerides, protecting them against hyperlipidaemia (abnormally elevated blood lipids), while having no known negative health consequences. Knockdown of the Angptl3 gene could therefore be an effective and safe way of treating hyperlipidaemia in humans, though more animal research will be needed before human clinical trials can be considered.
Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3: https://doi.org/10.1073/pnas.2020401118
LNP Delivers CRISPR Directly to Mouse Liver, Dramatically Cuts Cholesterol Levels for Months: https://www.genengnews.com/news/lnp-delivers-crispr-directly-to-mouse-liver-dramatically-cuts-cholesterol-levels-for-months/
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