ESPEYB19 14. Science and Medicine New treatments (2 abstracts)
14.13. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis
Julian D Gillmore , Ed Gane , Jorg Taubel , Justin Kao , Marianna Fontana , Michael L Maitland , Jessica Seitzer , Daniel O’Connell , Kathryn R Walsh , Kristy Wood , Jonathan Phillips , Yuanxin Xu , Adam Amaral , Adam P Boyd , Jeffrey E Cehelsky , Mark D McKee , Andrew Schiermeier , Olivier Harari , Andrew Murphy , Christos A Kyratsous , Brian Zambrowicz , Randy Soltys , David E Gutstein , John Leonard , Laura Sepp-Lorenzino & David Lebwohl
N Engl J Med. 2021 Aug 5;385(6):493–502. PMID: 34215024 doi: 10.1056/NEJMoa2107454. Epub 2021 Jun 26.
Brief Summary: 6 patients with hereditary, life-threatening transthyretin amyloidosis were treated with a novel in vivo gene-editing therapeutic agent (NTLA-2001) based on CRISPR-Cas9 technology. The new agent was given intravenously in a single dose and was able to durably knockout the responsible TTR gene and reduce the misfolded protein in the serum in a dose dependent manner over an observation period of 12 months.
Monogenetic transthyretin amyloidosis is caused by more than 100 mutations in the TTR gene, which cause the TTR protein to fold in a wrong shape and form clumps/fibers that interfere with organ function, especially in the heart and nerves. The disease is progressive and life limiting. So far, treatment consists of reducing amyloid formation by either stabilizing the tetrameric form of the TTR protein or by inhibiting its synthesis by degradation of the mRNA. However, these treatments are unsatisfactory for several reasons, including efficacy, side effects and need of long-term repeated administration.
So far, clinical trials had shown that the CRISPR-Cas9 technique can edit genes in cells that have been removed from the body and then reinfused back to the patients. This study is the first to show that the technique is safe and effective for treating a monogenetic disorder, when the CRISPR–Cas9 components are infused directly into the patients. Although promising, there are some limitations: Functioning of the technique depends on a DNA-cutting enzyme (Cas9), and a piece of guide RNA targeting the mutated gene. Thus the essential components must be packaged in a specific way that protects them from degradation and delivers them to the correct target body tissue or organ. Techniques for packaging and targeted delivery of CRISPR–Cas9 components to various parts of the body are improving. In the case of transthyretin amyloidosis, where the editing tools are needed in the liver, they were encapsulated into lipid nanoparticles, which are taken up by the liver from the circulation. It will be fascinating to follow how this technology might become applied to the treatment of other genetic conditions, even in later life.
Volume 19
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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