LETI-101 lowers mutant HTT protein in preclinical models
Mouse, cell models show proof-of-concept promise
LETI-101, an experimental gene-editing therapy for Huntington’s disease, showed promising proof-of-concept effects in mouse and cell models by reducing levels of the disease-causing mutant huntingtin (HTT) protein, while preserving HTT’s healthy version.
In nonhuman primates, the therapy showed good safety and distribution across brain regions profoundly impacted by Huntington’s.
The preclinical findings were shared by Life Edit, a subsidiary of Elevatebio, in a poster at the 20th Annual Huntington’s Disease Therapeutics Conference, held Feb. 24-27 in Palm Springs, California, in a poster titled “AAV5-delivered Life Edit CRISPR system results in broad CNS biodistribution and allele selective editing and reduction of mHTT protein in critical HD brain regions.”
Life Edit has received positive feedback from the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) on potential development pathways of LETI-101 for Huntington’s. “The compelling preclinical results being presented along with recent favorable feedback from the UK’s MHRA represent significant milestones in advancing LETI-101 as we explore partnership opportunities to accelerate the program’s progress,” Tedd Elich, PhD, Life Edit’s chief scientific officer, said in an Elevatebio press release.
Huntington’s is caused by mutations in one of the two copies of the HTT gene, which provides instructions to make the huntingtin protein. This leads to production of an abnormally long huntingtin protein, which is thought to drive the neurodegenerative disease.
Targeting mutant HTT protein
Given that the healthy version of the HTT protein has important cellular functions, a potential treatment strategy for Huntington’s is to selectively lower mutant HTT while sparing the healthy version.
LETI-101 is designed to do just that by taking advantage of the fact that the HTT gene has a common single nucleotide polymorphism (SNP), or a variation in a single nucleotide (DNA building block), called rs362331.
While people can have either a cytosine (C) or a thymine (T) in that specific nucleotide position of the HTT gene’s DNA sequence, about one-third of Huntington’s patients carry the T SNP on the mutated HTT copy, according to Life Edit.
LETI-101 uses a modified, harmless adeno-associated virus to deliver a DNA-editing technology called CRISPR designed to specifically target the T rs362331 SNP. This machinery contains Life Edit’s propriety nucleases, or DNA-cutting enzymes, guided by specific protospacer adjacent motifs (PAMs), or short DNA sequences, that target the T SNP.
By cutting DNA at the T SNP of the HTT gene, LETI-101 is expected to turn off the mutated copy of the gene while leaving the healthy version intact so that cells can still make healthy HTT protein.
LETI-101 is designed to work only on patients carrying the T SNP in the mutated HTT gene copy and the C SNP in the healthy gene copy.
“Our unique approach to selectively target the [mutant huntingtin] protein while preserving [the healthy version] is a clear example of the value of our diverse PAMs and robust collection of nucleases and demonstrates the broader capabilities of our platform to address other challenging genetic diseases,” Elich said.
Promising results
Researchers tested LETI-101 in lab-grown human cells and in a mouse model of Huntington’s in which only the mutated HTT gene copy carried the T SNP. Results in the cell model showed that the therapy led to a 55% drop in the levels of mutant HTT protein, while the healthy version of the protein was preserved.
In the mouse model, LETI-101 treatment was associated with dose-dependent editing of the target T SNP and clinically relevant reduction, by more than 40%, in mutant HTT protein levels in parts of the brain that are usually affected by Huntington’s.
In subsequent experiments in nonhuman primates, in which the therapy was administered directly into the brain via a surgical procedure, LETI-101 was found to be generally safe, with no obvious safety issues noted.
It was also shown to promote its gene-editing effects “across brain regions that are critically vulnerable in [Huntington’s disease],” the researchers wrote in the poster.
With these promising preclinical results, the therapy’s developers are now poised to start further studies that could support the submission of an investigational new drug application (IND), which is a formal request to U.S. authorities seeking permission to start clinical testing in people.
“The advancement of LETI-101 validates our gene editing technology and showcases Elevatebio’s ability to power the development of genetic medicines,” said David Hallal, Chairman and CEO of Elevatebio. “The progression of LETI-101 from concept to a partnership-ready development candidate poised to begin IND-enabling studies demonstrates the potential of this integrated approach, connecting technology, manufacturing, and therapeutics to change the future of medicine.”
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