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CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

The future is now … “clustered regularly interspaced short palindromic repeats” and associated Cas9 endonuclease aka CRISPR-Cas9 had its inception in 2012 and a Nobel prize awarded in 2020.

CRISPR is a powerful gene-editing technique first discovered in bacteria and adapted for permanent human gene knockout. While it has been extensively and exclusively used as a benchtop gene manipulation strategy finding great success as a research tool; however, its use as a therapeutic treatment modality seemed all but folklore, a bedtime story you tell your kids at night.

There has been a rush akin to the great California Gold Rush of 1848 to be the first biotech company to gain FDA approval for the first gene delivery therapeutic. This honor goes to Alnylam Pharmaceuticals for their short interfering RNA (siRNA) therapeutic ONPATTRO® (patisiran) FDA approved in August 2018. Patisiran was developed in a proprietary lipid formulation to treat transthyretin amyloidosis, also termed ATTR amyloidosis. ATTR amyloidosis is a very rare fatal disease that causes severe cardio and polyneuropathies and is characterized by the accumulation of amyloid fibrils consisting of misfolded transthyretin (TTR). Patisiran’s siRNA mechanism of action downregulates the production of TTR at a translational level facilitating the degradation of the messenger RNA coding for the misfolded TTR protein. The other entry into the arena of gene modulated ATTR amyloidosis therapy is TEGSEDI® (inotersen), approved in October 2018, and utilizes a frameshift mechanism to produce a nonfunctional TTR. These are mentioned because although they are gene therapies, their effects are transient.

NTLA-2001 is a new contender in the treatment of ATTR amyloidosis. NTLA-2001 is a lipid formulated CRISPR-Cas9 therapeutic that is currently being tested in a phase I clinical trial to treat ATTR amyloidosis. The researchers found that an infusion of either 0.1 or 0.3 mg/kg of NTLA-2001 in 6 patients, 3 in each group, reduced serum TTR levels by 52% and 87%, respectively. Interestingly, the formulation had minimal side effects and was tolerated exceptionally well. NTLA-2001’s claim to fame is two-fold. First, it is the first time CRISPR has shown clinical utility in a system other than a cell culture plate or an animal model.

Second, the effects of CRISPR are not as transient. It is the permanent removal of the affected genome. Although this study concluded at 28 days, their primate data showed TTR knockdown for up to 1 year.

Now you may wonder why ATTR amyloidosis and why are the first of its kind gene therapies targeted to treat a disease that potentially affects 50,000 people worldwide (0.0006% of the population). The answer is proof of concept, of course. The treatment of ATTR amyloidosis is the low-hanging fruit of gene therapy. The TTR protein is almost solely produced in the liver (>99.9%), and anything injected or delivered into the body eventually finds its way there. All roads lead to the liver. However, the introduction of gene therapies into the medicinal toolbox of clinicians is a pivotal step in the future of gene therapies that may in the future treat common disease states such as hypertension or hypercholesterolemia.

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Canan Schuman, PharmD/PhD
Author: Canan Schuman, PharmD/PhD

Canan Schumann is Chief Editor for Axxiem and for Axxiem's blog "BiotechOntheWeb". When not writing for Axxiem, Canan works as a Clinical Research Scientist II at the Research and Development Department at Molecular Testing Labs, developing endpoint assays for the detection of infectious disease and cancer. Canan currently resides in Portland, Oregon, where he received his Honors Bachelor of Science (HBS), Doctor of Pharmacy (PharmD.), and his Doctor of Philosophy (Ph.D.) in Biopharmaceutics at Oregon State University.