[Updated, 1/31/18, see below] Gene therapy pioneer James Wilson and University of Pennsylvania colleagues sounded an alarm Tuesday morning about the use of gene therapy to treat severe diseases like spinal muscular atrophy and Duchenne muscular dystrophy, sending a chill across the sector.
Shares of several companies inched downward as word spread about the UPenn work on Tuesday. Reached this afternoon, Wilson called for close monitoring of patients receiving high doses of a certain type of gene therapy delivered into the bloodstream.
Outside experts acknowledge that the studies were small but important. “The paper is getting the attention it deserves,” says Aravind Asokan, an associate professor of genetics and part of the gene therapy center at UNC School of Medicine in Chapel Hill, NC.
The findings raise questions about several experimental gene therapies in or not far from human trials. The paper, published in the journal Human Gene Therapy, reported that nerve and liver damage occurred in two separate animal tests of a potential gene therapy for SMA.
Specifically, the researchers saw one case of acute liver failure and shock in a monkey test, and damage to sensory nerve cells in both monkeys and piglets. One monkey and three piglets had to be euthanized.
Wilson and his team could not say if the results were specific to these tests or an indication of a broader problem. They concluded that “careful monitoring” is needed in similar settings—that is, when infusing a high dose of adeno-associated viruses (AAV) directly into the bloodstream to deliver genetic instructions.
Wilson (pictured), whose work on AAV technology has been crucial to the field’s development, was measured about these findings in a conversation late Tuesday. “AAV still remains, from my experience over three decades, one of the safest delivery systems,” he told Xconomy. “We should expect with any biologic product that if you push the dose high enough, you’re going to encounter dose-limiting toxicities.”
But Wilson also says seeing these side effects in two different studies with two different gene therapy products gave him pause. These problems have occurred amidst the rapid advance of gene therapy, with one product finally approved in the U.S. and several more in human trials. They’ve spurred his lab to publish the results as quickly as possible.
“We are seeing some indications of what you may want to monitor if you are in that space,” he said, citing immediate bleeding or a rapid spike in liver enzymes, for example. “I would encourage those involved in these studies to monitor their research subjects.”
The problems reported in the paper have not yet occurred in human tests of AAV gene therapies. Many have shown promise and in some cases stunning results for several different diseases. The most common side effects have been delayed immune reactions that are easily contained with a short course of steroids.
It’s possible the side effects Wilson and colleagues saw “are not applicable to humans, are only related to the specific variants [in] Dr. Wilson’s lab, and/or are related to manufacturing impurities,” RBC Capital Markets analyst Brian Abrahams wrote in a research note Tuesday.
The UPenn team notes in the paper that its studies offer “provocative but incomplete evidence for a unifying mechanism of toxicity.”
Still, the paper is cause for concern. “I think dose-finding studies and very careful clinical design are going to be critical,” said UNC researcher Asokan.
[Updated with comments from Vandenberghe] Luk Vandenberghe, the director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear, said that because the study showed the “first clear documentation of [high] toxic doses with AAV,” the results “cannot be ignored, and are important as they set a dose range for the field to be on the lookout for toxicity.”
Vandenberghe—a listed inventor on the patent for AAV9, one of the AAV variants being delivered in human clinical tests, systemically, at high doses—added that the study highlights the need to standardize how gene therapy products are characterized. Until that happens, researchers can’t compare one gene therapy program to another or, in this specific case, how UPenn’s findings “impact ongoing and pending clinical programs.”
Safety incidents, such as the death of teenager Jesse Gelsinger in 1999 in a trial co-led by Wilson, chilled investment in gene therapy work for years. But Wilson and many others plugged away on the underlying technology, and now there are several AAV therapies in development that put high doses directly into the bloodstream to reach skeletal muscle, the brain, and other tissues.
Among those fitting this description is a gene therapy from Chicago-based AveXis (NASDAQ: [[ticker:AVXS]]), for a deadly form of SMA affecting infants, that is in late-stage testing. Gene therapies from Sarepta Therapeutics (NASDAQ: [[ticker:SRPT]]), Solid Biosciences (NASDAQ: [[ticker:SLDB]]), and Pfizer (NYSE: [[ticker:PFE]]) for Duchenne muscular dystrophy have recently begun human trials or are about to start. There are others in development, like a treatment from Audentes Therapeutics (NASDAQ: [[ticker:BOLD]]) for the rare X-linked myotubular myopathy, or the Abeona Therapeutics (NASDAQ: [[ticker:ABEO]]) treatment for Mucopolysaccharidosis IIIB.
In a statement to Xconomy, AveXis
