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Fix Discovered for Gene Therapy Virus Delivery

Adeno-associated virus

Adeno-associated virus (Jazzlw, Wikimedia Commons)

2 June 2020. Researchers in France and the U.S. discovered a bacterial enzyme that blocks immune reactions to otherwise benign viruses that deliver gene therapies. A team from biotechnology company Spark Therapeutics in Philadelphia and three research institutions in Paris report their findings in yesterday’s issue of the journal Nature Medicine (paid subscription required).

Spark Therapeutics develops treatments for inherited diseases that transfer healthy genes into patients to replace their mutated or damaged versions. These transfers are made with engineered adeno-associated viruses, or AAVs, benign and naturally occurring microbes that can infect cells, but do not integrate with the cell’s genome or cause disease, other than at most mild reactions. These viruses, however, can also trigger immunoglobulin G antibodies in the immune system that neutralize the viruses, preventing delivery of healthy genes.

Researchers led by Spark’s chief scientist Federico Mingozzi tested a protein called imlifidase as a way to protect adeno-associated viruses from these antibodies. Imlifidase or IdeS is an enzyme produced by Streptococcus pyogenes bacteria, the same bacteria responsible for strep throat, scarlet fever, and other diseases. The enzyme is an endopeptidase, a class of enzymes that cleaves peptide bonds, in this case the peptides making up the immunoglobulin G antibodies neutralizing adeno-associated viruses.

Mingozzi and colleagues evaluated imlifidase against these antibodies in a series of lab and animal tests. In lab tests, the team found imlifidase cleaves immunoglobulin G antibodies in samples of human blood plasma, including samples from prospective gene therapy patients.

The researchers also tested imlifidase in lab mice, and monkeys induced with the inherited disease hemophilia, an inherited disorder where blood does not clot adequately, resulting in spontaneous or uncontrolled bleeding. In hemophilia, a genetic defect fails to produce proteins needed to mix with platelets allowing blood to coagulate. About 8 in 10 people with the condition have hemophilia type A, where the protein clotting factor 8 is missing. In type B, clotting factor 9 is missing.

With monkeys, the researchers assessed gene therapies transferring healthy genes to the liver correcting both types of hemophilia, but the test monkeys received imlifidase before the adeno-associated viruses carrying the healthy genes. The results show gene therapies delivered to monkeys first receiving imlifidase are safely and efficiently processed in the liver. The imlifidase blocks formation of immunoglobulin G antibodies, allowing delivery of the healthy genes that lead to expression of factor 8 and 9 proteins in liver cells.

“One of the main challenges associated with AAV-mediated gene therapy is neutralizing antibodies that can impact the ability to administer gene therapy,” says Mingozzi in a company statement. “The IdeS technology has the potential to eliminate anti-AAV antibodies that allow for the extended use of gene therapy in a larger segment of candidates who may have been excluded due to pre-existing or developing neutralizing antibodies and also enable vector re-administration.”

Spark Therapeutics is a pioneer in gene therapies, founded among others by Katherine High, professor of pediatrics at University of Pennsylvania who studies hemophilia, who became the company’s president and recently returned to the university. The company’s pipeline includes treatments for hemophilia A and B, now in clinical trials. As reported by Science & Enterprise in February 2019, Spark was acquired by drug maker Roche Group in a deal valued at $4.3 billion.

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