Gene-editing Therapy for ATTR Shows Promise in Preclinical Study

Precision BioScience’s gene-editing therapy for transthyretin amyloidosis (ATTR), a group of disorders that also encompasses familial amyloid polyneuropathy (FAP), shows therapeutic potential in a preclinical study.

Data from the study will be presented by Jenny A. Greig, PhD, senior director of the Gene Therapy Program at the Perelman School of Medicine, University of Pennsylvania, in the poster (No. 497) titled “Translation of an AAV-delivered gene editing approach for transthyretin amyloidosis from mice to nonhuman primates,” at the virtual American Society of Gene & Cell Therapy Annual Meeting, running May 11–14.

ATTR is caused by the buildup of misfolded transthyretin (TTR) protein in different tissues and organs. In FAP, the production of the faulty protein is a direct result of genetic mutations in the TTR gene, which provides instructions for making TTR.

Problems in the structure of TTR cause it to clump together, forming toxic protein deposits (amyloid fibrils) that disrupt tissue and organ function. The heart and nerves tend to be most affected by the disease.

Gene-editing therapies, which target the TTR gene in liver cells leading to its permanent inactivation, are an attractive strategy for ATTR, especially because they usually are a one-time treatment. This is in contrast to currently approved disease-modifying therapies, such as Onpattro (patisiran) and Tegsedi (inotersen), which require multiple administrations to be effective.

Gene therapies often use adeno-associated viruses (AAVs), which are modified in the lab to become harmless, as delivery vehicles.

In the study, researchers assessed the effectiveness of a gene-editing therapy that delivers a member of the ARCUS nucleases — molecular DNA scissors — designed to specifically cut a portion of the TTR gene, leading to its permanent inactivation, a strategy known as knockout gene editing.

The nuclease, called TTR15-16, targets a region within the TTR gene that is conserved in rhesus macaques and humans, but is lacking in mice.

Thus, before performing tests in nonhuman primates, the researchers tested the gene-editing therapy in mice which were previously genetically modified to harbor the human version of the TTR gene in liver cells. Animals were then treated with one of three doses of the therapy, which was given intravenously (into the vein).

Results showed a decrease in the levels of human TTR with increasing doses of the therapy. When given at a dose of 3×10¹¹ genome copies per kilogram (GC/kg), the therapy lowered the levels of human TTR by 94.5%. In mice treated with the higher dose (3×10¹³ GC/kg), human TTR was nearly absent, with levels dropping by 99.9%.

The researchers then evaluated the gene-editing therapy in rhesus macaques. Eighteen days after treatment, liver biopsies of the animals showed that when given at a dose of 3×10¹³ GC/kg, the therapy successfully targeted and modified the TTR gene in their liver cells. The researchers observed a marked reduction (greater than 95%) in the levels of TTR in the animals’ blood 21 days after treatment.

These results showed that this ARCUS nuclease was “effective in both mice and nonhuman primates, where we observed a good correlation between TTR gene editing in the liver and reductions of TTR in the serum,” Derek Jantz, PhD, chief scientific officer and co-founder of Precision BioSciences, said in a press release.

Compared to similar gene-editing therapies delivering nucleases, the number of off-target effects — genes other than TTR that end up being altered — were reduced.

Overall, “the significant reduction in serum [blood] TTR levels following genomic editing of the TTR gene by the TTR15-16 meganuclease expressed from an AAV vector indicates that this approach could be effective for the treatment of ATTR,” the researchers wrote.

“This approach addresses the root cause of the disease and results in genomic edits that are expected to be permanent,” Jantz said. “These results continue to demonstrate the power and versatility of ARCUS nucleases, particularly for in vivo editing.”