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Trial Shows In-Body Crispr Therapy Feasibility

Crispr genome edits illustration

(NIH.gov)

28 June 2021. Early clinical trial data show gene editing with Crispr performed inside the body can correct an inherited neurological condition, with few adverse effects. Researchers from the biotechnology company Intellia Therapeutics Inc. in Cambridge, Massachusetts and Regeneron Pharmaceuticals Inc. in Tarrytown, New York report their findings in Saturday’s issue of New England Journal of Medicine. The results were also presented at the annual meeting of Peripheral Nerve Society.

Crispr, short for clustered, regularly interspaced short palindromic repeats, is adapted from a natural process used by bacteria to protect against attack by viruses, where an enzyme that deactivates or replaces genes binds to targeted RNA molecules generated by the genome. The RNA molecules then guide the editing enzyme, known as Crispr-associated protein 9 or Cas9, to specific genes needing changes.

Intellia is developing therapies with Crispr-Cas9 that remove disease-causing genes or mutations, repair genes with mutations found in small regions of DNA, and insert corrected or functioning genes when mutations are found in larger DNA regions. The company says its treatments are being designed to be either administered directly to work in vivo, i.e.  inside patients’ bodies, or delivered to cells taken from the patient, then cultured outside the body and transplanted back.

The clinical trial is testing a Crispr-Cas9 therapy for the inherited disease transthyretin amyloidosis, a rare disorder caused by a mutation that interrupts instructions to produce in the liver a protein called transthyretin. Without transthyretin, or TTR, another protein called amyloid builds up on organs, tissues, and nerves in the body, affecting functions of the peripheral nervous system and other organs.

Lower TTR protein levels at higher doses

Intellia and Regeneron began a collaboration in 2016 to develop in vivo therapies with Crispr-Cas9, with transthyretin amyloidosis as one of the early targets. The early-stage trial is enrolling 38 adult participants with the disorder, looking primarily for safety of the Crispr-Cas9 therapy code-named NTLA-2001, given as a single infusion in four different doses, as well as changes in TTR protein levels in participants. The study team is tracking participants for up to two years.

The paper reports results from the first six participants, given one of two doses, and followed-up after 28 days. The results show few adverse effects of the treatments, and those that occur are mild in nature. Findings also show participants with lower concentrations of TTR protein in the blood, from 52 to 87 percent average reductions. Those receiving the higher dose of NTLA-2001, 0.3 milligrams per kilogram of patient weight, report larger TTR reductions than recipients of the lower dose, 0.1 milligrams per kilogram of weight.

“These are the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of Crispr,” says Intellia’s president John Leonard in a statement. Leonard adds, “Solving the challenge of targeted delivery of Crispr-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline.”

The clinical trial is continuing with tests of NTLA-2001 at higher doses, then assessing the optimal dose level in patients with transthyretin amyloidosis.

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