Interim Phase 1 data reveal that treatment with the novel CRISPR-Cas9 gene editing therapy NTLA-2001 resulted in a fast response in individuals experiencing transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM).
With a continuous administration of NTLA-2001 at 2 distinct dosages, serum of the genetic disorder TTR protein was lowered by at most 90% by day 28, with decreases lasting 4 to 6 months. In participants with New York Heart Association (NYHA) Class I-III heart failure, NTLA-2001 was usually well tolerated, and results were comparable, following the report from Medspace.
As remarked by Julian Gillmore, MBBS, MD, Ph.D., who is directing the project at University College London, such evidence supports and expands the initial results indicating the potential of CRISPR-based in vivo genetic modification in humans. In particular, the profound TTR reductions reported in this trial in individuals with ATTR amyloidosis provide a real chance for meaningful therapeutic improvement in a syndrome that has remained progressive and usually fatal too far, he stated.
TTR protein mutations
The findings were revealed at the American Heart Association (AHA) Scientific Sessions 2022 in a late-breaking presentation.
TTR protein mutations genetic and age-related alterations in the structure of the TTR peptide can cause misfolding, resulting in amyloid plaques in the skin as well as heart muscle tissue. It is estimated that 50,000 persons globally have hereditary ATTR amyloidosis, with up to 500,000 having wild-type ATTR amyloidosis. Amyloid cardiomyopathy is unexplained and, if left untreated, results in mortality within three to ten years. He claims that existing therapeutic approaches simply postpone progression and need lifetime maintenance, as reported by Healio.
The study's polyneuropathy arm was announced last year, and the findings were heralded as a triumph as well as further evidence of the idea that CRISPR may be used to treat various disorders. CRISPR genetic manipulation has been shown to be effective in -thalassemia as well as sickle cell disease, however, it requires stem cells to be removed from patients' bone marrow, handled in the facility, and then restored. NTLA-2001 (Intellia Therapeutics/Regeneron) represents an in vivo therapy that employs lipid nanoparticles carrying Cas9 messenger RNA and a single-guide RNA that binds TTR in the liver, where it is virtually entirely generated.
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Early Laboratory Findings
The current study comprised 12 heart failure patients: three from NYHA Classes I-II and six from NYHA Class III, who got a single dosage of NTLA-2001 at 0.7 mg/kg, whereas the rest of the group from NYHA Class I-II were given one dose of 1.0 mg/kg. Eight individuals had mild to moderate adverse events, and two had transitory infusion responses, which included a Grade 3 response in the 0.7 mg/kg NYHA Class III category, which cleared without clinical sequelae. Per the research protocol, this group was increased to six patients. Gilmore stated that no more Grade 1 procedure abnormalities were reported and that no further dosage increase was performed.
There weren't any clinically significant laboratory results; however, one patient experienced a temporary Grade 1 rise in liver enzymes. The possibility for off-target consequences is a disadvantage of CRISPR, however, Gillmore stated in an interview that medication developers went through a really rigorous procedure that really strives for the selectivity of the RNA when picking the guide RNA TTR Gene.
In terms of additional future hurdles, Gillmore also mentioned that it has to be observed whether the knockdown obtained will convert into more therapeutic benefit. Still, because ATTR is a chronic illness, there is an unmet need to create medicines that can prevent or reverse disease, be efficacious in advanced ATTR, and have a better route of distribution or frequency of administration, he added following a report from Local Today.
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