Academia, Gene Therapy

Gene therapy pioneer James Wilson sounds an alarm on high-dose AAV studies following toxic reactions in monkeys

James Wilson. Penn News

Penn professor James Wilson is one of the preeminent scientists working today in gene therapy. He’s also the key figure in a fatal gene therapy trial back in the late ’90s that left the field in limbo for years, until a new generation of biotechs hustled ahead with the current wave of vector-carried corrective genes in the clinic — with an historic first approval in the US for Spark.

So when it surfaced that Wilson had quit an advisory role at Solid Bio $SLDB over safety issues associated with high-dose AAV gene therapy treatments — which coincided with a partial FDA hold on Solid’s high-dose work that was announced just hours before it priced its $125 million IPO — that sounded an alarm to some people in the field.

On Monday, Wilson and his team unveiled the reasons for his safety concerns in an online publication of a new animal study that outlined their use of a high-dose AAV delivery of a corrective gene for the survival of motor neuron (SMN) protein.

Following successful work involving infants with spinal muscular atrophy, a link that also dinged AveXis $AVXS today, Wilson and his team at Penn wanted to see how the same approach could correct a genetic deficiency of lower motor neurons — a condition linked to neuromuscular diseases.

The animal study, using three rhesus macaque monkeys and three pigs, was a toxic disaster.

Four days after one of the macaques had received 2×1014 GC/kg AAVhu68 vector expressing human SMN, the monkey experienced a severe crisis, going into shock after suffering severe liver damage, which forced researchers to euthanize the primate. The two other macaques survived, but also suffered a toxic reaction.

All three piglets treated with a high, systemic IV dose were also euthanized, with the first experiencing ataxia and the other two responding with neurological symptoms.

“The adverse events observed in these two NHP (nonhuman primate) studies provide provocative but incomplete evidence for a unifying mechanism of toxicity resulting from high dose systemic AAV administration,” the team writes. “Findings common to both experiments include hepatocellular injury and development of a bleeding diathesis consistent with DIC within 5 days of vector administration. It is presently unclear whether liver damage is the primary insult leading to the coagulopathy, or if the coagulopathy is a manifestation of systemic toxicity that results in secondary liver damage.”

And there’s this:

Going forward we suggest that clinical trials of high dose systemic AAV include careful pre‐clinical vetting in NHPs and early laboratory and clinical evaluations for systemic toxicity, liver damage, and coagulopathy as well as delayed symptoms of sensory neuropathy.

Solid Bio says it is out to cure Duchenne MD using a gene therapy. And after seeing its IPO get started with a quick peak, the stock slipped from its high but was still trading well over its initial price. As news of the study spread, though, the stock plunged 12% on Tuesday. Shares of Regenxbio $RGNX, where Wilson has provided much of the AAV patent work, slid 4%.

Whatever worries Wilson may have now about high-dose AAV work, the biotechs in the field have yet to see much of it spread among the investors who back their companies.


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