2:30 PM
Feb 02, 2018
 |  BioCentury  |  Product Development

AA Viral meme

James Wilson’s findings on AAV toxicity should have limited impact on the vectors’ use in humans

Gene therapy pioneer James Wilson’s revelation of two new types of toxicity in animals receiving high systemic doses of adeno-associated viral vectors is unlikely to herald a major disruption of the AAV space, though it remains to be seen whether they influenced his decision to resign as SAB chair of Solid Biosciences Inc.

Wilson plus five AAV researchers who spoke with BioCentury concurred that any repercussions likely would be limited to a handful of products given at high systemic doses to treat neurological or musculoskeletal disorders in children.

The threshold for safe dosing will likely depend on product-specific characteristics.

“The overwhelming majority of gene therapy applications that are being considered in the clinic I don’t think are really impacted by these findings,” Wilson told BioCentury.

“The overwhelming majority of gene therapy applications that are being considered in the clinic I don’t think are really impacted.”

James Wilson, University of Pennsylvania

Wilson’s lab group from the University of Pennsylvania presented the animal findings in a Jan. 30 publication in Human Gene Therapy.

Wilson told BioCentury the toxicities arose when his group pushed AAV doses beyond the norm of most therapeutic applications to test the safety of the high vector quantities needed to reach large amounts of muscle or cross the blood-brain barrier.

In particular, the researchers saw a liver toxicity unlike that customarily seen with AAVs because it was accompanied by systemic inflammation and coagulopathy. Both conditions were features of the pathology that led to the death of Jesse Gelsinger in a 1999 gene therapy trial at UPenn, where Wilson is a professor and director of the gene therapy program.

Rather than abandon the therapies altogether, Wilson and the researchers contacted by BioCentury suggested the field should take a more cautious approach to human development while work continues to identify the threshold of toxicity.

Eventually, engineering improvements to vectors to deliver the transgene more efficiently to the target tissue or with less immunogenicity could reduce the risk that newer AAVs will cross that threshold.

The SGT-001 issue

It’s unclear the extent to which Wilson’s findings may apply to Solid, which is developing its SGT-001 gene therapy to treat Duchenne muscular dystrophy (DMD).

SGT-001 is delivered by a serotype AAV9 vector designed to stabilize the dystrophin glycoprotein complex by delivering microdystrophin. It is one of three AAVs delivering versions of dystrophin that entered human trials toward the end of 2017. The others are Nationwide Children’s Hospital’s rAAVrh74.MHCK7.micro-dystrophin and Pfizer Inc.’s PF-06939926.

Sarepta Therapeutics Inc. has an exclusive option to the Nationwide program under a 2017 deal. Pfizer gained PF-06939926 when it acquired Bamboo Therapeutics Inc. in 2016.

Gene therapy for musculoskeletal disorders like DMD may require unusually high doses of vector given systemically to overcome their tendency to concentrate in the liver, even with modifications designed to improve uptake in muscles.

On Jan. 25, Solid raised $125 million in a downsized IPO that valued the biotech at $546.4 million.

In a series of amended S-1 filings released in January ahead of the offering, Solid disclosed Wilson’s resignation over “emerging concerns about the possible risks of high systemic dosing of AAV.”

The disclosures also included the death of a non-human primate in an SGT-001 toxicology study, and a partial clinical hold barring administration of the higher intended dose in Solid’s Phase I/II IGNITE DMD study until the company resolves manufacturing concerns.

Solid declined to comment, citing the IPO quiet period.

A call for caution

In the Human Gene Therapy report, Wilson’s team identified new and severe toxicities in non-human primates and piglets given high doses of systemic AAVs.

All the animals received 2x1014 viral genomes per kg (vg/kg) of an AAVhu68 vector expressing human survival of motor neuron 1 telomeric (SMN1) protein. AAVhu68 is a serotype variant that differs from AAV9 by two amino acids.

All three rhesus macaques in the study experienced liver enzyme elevations. Two cases resolved spontaneously. The third developed liver failure and shock, for which it was euthanized. That subject showed evidence of liver necrosis, systemic inflammation and disseminated intravascular coagulation.

Clinically asymptomatic neurodegeneration of the dorsal root ganglia occurred in all three primates.

“I think there’s enough evidence in the hemophilia trials that at lower doses, AAV is probably going to be surprisingly safe.”

George Dickson, Royal Holloway University of London

None of the three piglets showed signs of hepatotoxicity. But all experienced sensory deficits and ataxia that impaired walking that “necessitated euthanasia,” according to the report.

While the mechanisms behind the toxicities are still being sorted out, Wilson told BioCentury the hepatotoxicity appears to have an immune component unlike that previously seen in AAV trials, where hepatotoxicity has been common but rarely, if...

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