In the wake of recent headlines on Clinical Blockages in Gene Therapy Trials, the FDA’s two-day Adeno-Associated Virus (AAV) Vectors Safety Hearing examined the complex issues posed by the administration.
At Thursday and Friday, the agency’s Cell, Tissue and Gene Therapies Advisory Committee (CTGTAC) organized sessions on the risk of oncogenesis, liver toxicity, and thrombotic microangiopathy in AAV vectors for gene therapy, culminating in two sessions on neurotoxicity: one on dorsal root ganglia (DRG) toxicity and one on brain MRI results.
Like carcinomas, neuronal damage associated with AAV vectors has emerged mainly in preclinical data. Toxicity in sensory neurons of DRG has largely not been reported in humans, but in non-human primates administration of AAV through the cerebrospinal fluid (CSF) and intravenously has been reported. associated with axonal degeneration in some pathways of the spinal cord and peripheral nerves.
One factor that appears to make a difference in the severity of axonal degeneration is the transgene itself, noted guest speaker James Wilson, MD, PhD, of the Perelman School of Medicine in Philadelphia and a pioneer in gene therapy research. Decreased expression of the transgene in cells that express microRNA that is present almost exclusively in DRG can reduce pathology, he added.
It is not clear how the toxicity of DRG clinically affects non-human primates. Of the 483 animals treated by Wilson’s group, neurological findings appeared in five: four were mild and reversible, and one was severe and required euthanasia.
In these studies, the researchers were unable to measure nerve conduction velocity (PNV), but other gene therapy research showed that the animals rarely had abnormalities in CNV. “I realize this is anecdotal, but in this study it appears that NCV may be a good measure of what’s really going on from a pathological standpoint,” Wilson said. NCV evaluations have been limited in human trials so far, but have been used more in recent studies, he pointed out.
If an animal was suffering from paresthesia, it would be difficult to know, Wilson added. Likewise, some humans who receive AAV vectors may experience pain or neuropathic symptoms and not be able to express it – especially young patients or people with cognitive or motor problems – the limbs observed. committee, agreeing that closer monitoring is needed.
The new AAV treatment should carefully study neurotoxicity, said Raymond Roos, a member of the temporary voting committee, University of Chicago: “In the case of humans, nerve conduction velocities or MRIs might be useful before. and after administration of AAV. “
Brain MRI results
Intraparenchymal administration of AAV vectors has been evaluated in several disorders, including a form of Batten disease known as CLN2 disease, said guest lecturer Ronald Crystal, MD, PhD, of Weill Cornell Medical College in New York City. .
While children with CLN2 disease benefited from AAV vector gene therapy, showing less decline in motor and language ratings than similar children in a natural history study, brain damage appeared on the brain. MRI, he observed.
“What we noticed was that there were MRI abnormalities at the end of the catheter,” Crystal said. The finding had no clinical correlates but was consistent with localized inflammation or edema, he said.
“There have been no other significant adverse events that we can relate directly to the vector in these children,” Crystal said. One aspect of CLN2 disease is chronic seizures, so in the short term, adverse events can be difficult to assess, he noted.
“It is not known whether systemic immunosuppression can suppress an inflammatory / immune response such as the type we have seen,” he added. “I think this is something that needs to be investigated in the future.”
Changes in MRI have been shown in other studies where an AAV vector was injected directly into the brain. Last year, the FDA put a Voyager on clinical hold. Parkinson’s disease gene therapy trial after some participants showed abnormalities on the MRI, for example, but the significance of those results was unclear. Even in Parkinson’s disease, “it appears that we need new, innovative technical approaches to AAV vector delivery,” Roos suggested.
The imaging changes on the MRI appear to be minor, some committee members noted. Vector tracing and other investigations in non-human primates may help clarify MRI abnormalities, others added. MRI-guided infusions and follow-up MRIs at regular intervals may also alleviate potential CNS damage in humans.
“In all of these cases, we need to keep the issues of risk and benefit in mind,” Roos noted. “This could be particularly the case in certain progressive and difficult to treat human central nervous system diseases.”