Potential Gene Therapy Safely Restores FVIII Clotting Factor in Animals and Human Cells, ASC Therapeutics Reports

A gene therapy being developed by ASC Therapeutics restored levels of the clotting factor missing in hemophilia A in a mouse model of the disease, and further tests in primates and human cells suggest the therapy might also work for people, the company announced.

Results from these preclinical studies were presented at the 22nd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in three presentations, titled: “Hemophilia A Cured in Mice by CRISPR-based In Vivo Genome Editing of Human Factor FVIII (abstract 999),” “Site-Specific Genome Editing by CRISPR/ Cas9 for Hemophilia A in Human and Non-Human Primate Cells (abstract 507),” and “Adeno-Associated Virus Serotypes Screening in Non-Human Primates for Hemophilia A Genome Editing Treatment (abstract 191).”

Hemophilia A is caused by mutations in the gene holding the instructions to produce blood clotting factor VIII (FVIII), and is mainly treated with therapy that replaces that missing or faulty factor, via regular injections of a lab-made version of FVIII into the bloodstream.

ASC’s therapy uses the genome-editing tool CRISPR-Cas9 to insert a healthy copy of the FVIII gene into specific cells that than produce a working clotting factor. The company is a division of Applied StemCell, both based in California.

CRISPR-Cas9 protocol allows replacing the DNA sequence at a specific region of the genome — the whole set of DNA present in an organism — by a particular DNA fragment produced in the lab. The genome of the treated cells is edited permanently, so that a single treatment causes a permanent change.

In these preclinical experiments,  researchers replaced the gene instructing production of albumin — the most abundant protein in human blood — with one guiding production of functional FVIII in a group of liver cells in living mouse model of hemophilia. They were testing whether the edited cells could produce functional clotting factor and deliver it into the bloodstream in ways similar to what happens with albumin.

Treated mice responded as hoped, producing FVIII in their livers and effectively transporting it into the blood, raising the clotting response and significantly reduced the number of bleeding episodes. A working factor was sustained for seven months without causing toxicity to the liver, and no adverse events were linked to components of the therapy, the study reported.

Researchers also gene-edited in the lab cells from rhesus macaque (a monkey) and human liver cells using the same approach, and observed a good response without evidence of problems. These results suggest that this approach has a potential to work in people.

Finally, the team conducted studies in 16 long-tailed macaques to investigate possible side effects caused by the carrier molecules used to deliver the therapy, two versions of a safe and inactivated form of the adeno-associated virus (AAV) family commonly used in gene therapies. The monkeys were reported to show no evidence of toxicity or specific immune responses caused by the therapy.

“Based on these findings, our genome editing approach (…) may offer an efficacious, long-term, and safe treatment for patients with hemophilia A,” the researchers said.

The team is now testing this therapy in humanized mice models of hemophilia A, which better mimic features of the human disease. Additional experiments are also underway to better assess the  investigative therapy’s effectiveness.

“We are very proud of the achievements and rapid progress our therapeutics team has made thus far. We have learned a great deal from these initial studies, which we will leverage as we move forward into the next phase,” Ruhong Jiang, CEO and founder of ASC, said in a press release.