team of researchers from Intellia Therapeutics, Inc. and Regeneron
Pharmaceuticals has conducted the first clinical trial involving in vivo
CRISPR human gene editing. In their paper published in The New England Journal of Medicine,
the group describes developing a CRISPR technique for treating
transthyretin amyloidosis (ATTR amyloidosis) patients and administering a
therapy called NTLA-2001 to six patients as part of a Phase 1 clinical
Transthyretin amyloidosis (ATTR amyloidosis) is an inherited genetic disorder that involves TTR misfolded proteins—patients with it experience painful protein build-up around nerve cells—in
most cases, it is progressive and fatal. In this new effort, the
researchers sought to treat such patients by editing the TTR genes in
ways that made them mimic patients that do not have the disorder.
therapy consisted of lipid nanoparticles carrying the genome editor to
the liver. The first part of the process involved guidance to the genes
to be edited while the second part involved using RNA messaging to
conduct the gene edits. In the trial, the patients were divided into
groups, with each receiving a different dose of the NTLA-2001 therapy.
Testing of the patients afterward showed that those who received 0.1 mg
of the therapy saw reductions in TTR protein levels of 52%. Those who
received a 0.3 mg dose saw an average decrease of 87%.
researchers note that the results for the patients receiving the higher
dose outperformed patients who receive a drug called patisiran to treat
their symptoms—such patients on average see an 80% reduction in TTR
protein levels; not enough to prevent the progression of the disease.
They also note that their approach requires one dose, while patisiran
must be given regularly. The researchers also found that none of the
patients in the clinical trial reported any adverse reactions to the
researchers suggest that their therapy approach merits further
testing—the next step will be to give patients higher doses of NTLA-2001
to see if it will reduce protein levels to the point that it stops the
progression of the disease. If these tests are successful, the group
plans to test the therapy on larger numbers of patients.
More information: Julian D. Gillmore et al, CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis, New England Journal of Medicine (2021). DOI: 10.1056/NEJMoa2107454