CRISPR is a gene-editing technology which holds the potential to treat a variety of genetic diseases and improve patient outcomes. Overall, CRISPR works by creating precise cuts and edits within cell genomes, addressing underlying genetic issues. Typically, this is done ex vivo, or outside of the body; cells are removed, edited, and then returned. However, an ongoing Phase 1 clinical trial, spearheaded by Regeneron Pharmaceuticals (“Regeneron”) and Intellia Therapeutics (“Intellia”) is the first of its kind to evaluate a CRISPR candidate (NTLA-2001) in vivo.
Recently, Intellia and Regeneron shared interim data from the first six patients with ATTR amyloidosis who were treated with NTLA-2001. Ultimately, the data highlighted how CRISPR appears to be both safe and effective when injected straight into the bloodstream. See the full set of findings, entitled “CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis,” published in the New England Journal of Medicine.
Hereditary ATTR Amyloidosis
There are six main types of amyloidosis, a condition in which abnormal amyloid proteins accumulate – and form deposits – within the body. As the amyloid deposits accumulate in organs, like the heart or kidneys, the organs stiffen and lose function.
TTR gene mutations cause hereditary ATTR amyloidosis, which often affects the heart and nervous system. These genetic mutations cause transthyretin (TTR) protein to form abnormally, creating deposits throughout the body. ATTR amyloidosis may be senile systemic, familial amyloid cardiomyopathy (FAC), or familial amyloid polyneuropathy (FAP). Symptoms depend on where the protein deposits accumulate.
ATTR Amyloidosis Symptoms
For example, patients with amyloid deposits in the heart may experience:
- Nausea and vomiting
- Unintended weight loss
- Shortness of breath
- Dizziness and fatigue
- Swelling of the legs
- Chest pain
- Atrial fibrillation
Alternately, those with an impacted nervous system could experience peripheral and autonomic neuropathy, as well as sensorimotor impairment. If the digestive system or kidneys are affected, symptoms include:
- Nausea and vomiting
- Diarrhea or constipation
- Unintended weight loss
- Abdominal swelling
- Feeling of fullness (even after eating small amounts)
- Appetite loss
- Swelling of the legs, lungs, and arms
- Issues with bladder control
- Proteinuria (excess protein in the urine)
- Renal failure
Learn more about ATTR amyloidosis.
NTLA-2001
Within the study, researchers treated six patients with intravenous NTLA-2001. As described in a prior press release from Intellia:
Based on Nobel Prize-winning CRISPR/Cas9 technology, NTLA-2001, [the first experimental CRISPR therapy to be administered systemically…to edit genes inside the human body], could potentially be the first curative treatment for ATTR. Intellia’s proprietary non-viral platform utilizes lipid nanoparticles designed to deliver to the liver a simple, two-part genome editing system: guide RNA specific to the disease-causing gene and messenger RNA that encodes the Cas9 protein.
Patients in this trial received either 0.1mg/kg or 0.3mg/kg NTLA-2001. Next, researchers evaluated TTR protein levels in blood serum over the next 28 days (approximately 1 month). Researchers determined that:
- NTLA-2001 was safe, effective, and well-tolerated. Thus far, no serious adverse reactions occurred.
- In patients receiving 0.1mg/kg, scientists saw a mean TTR reduction of 52%. Alternately, the 0.3mg/kg treatment reduced TTR levels by a mean of 87%, with one patient even achieving 96% lower levels.
- The outcomes achieved in this trial show similar efficacy to patisiran, the current standard-of-care for ATTR amyloidosis. Normally, patisiran reduces TTR levels by 80%. However, while patisiran requires multiple and ongoing doses, NTLA-2001 requires only one.
In later studies, researchers hope to determine whether higher doses (1mg/kg) could be even more effective.
