New Gene Therapy Could Be Toxic

[Gert van der Hoek]

Why A Gene Therapy Pioneer Is Raising Concerns About Treatments He Championed


FEB 7, 2018

Jim Wilson has been one of gene therapy's pioneers. Now he's raising concerns about the safety of a technology he helped develop – at least when it is pushed to its limits. In two new studies his team conducted in monkeys, high doses of a certain type of gene were toxic.

"I recognize the fact that these are limited numbers [of animals], and in fact that studies were not designed to evaluate safety," Wilson says in an interview with Forbes, reproduced below. "But the fact is, we observed the toxicity with that limited number, which is, from my point of view, even more worrisome."

We conducted two different animal studies in non-human primates and in pigs to study the efficacy of high-dose intravenous AAV to target the central nervous system. We did not expect to see any safety concerns because of the incredible safety track record that AAV has had.

But what we indeed saw in both studies was that, at very high doses, the animals developed within the first few days after the vector was injected evidence for some liver damage and also activation systemically of inflammation, the consequences of which, was the development of a bleeding disorder or coagulopathy.

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[Gert van der Hoek]

Hum Gene Ther. 2018 Jan 29. doi: 10.1089/hum.2018.015. [Epub ahead of print]

Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMN.

Abstract

Neurotropic AAV serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously at high doses. This observation led to the recent successful application of intravenous AAV9 delivery to treat infants with spinal muscular atrophy (SMA), an inherited deficiency of the survival of motor neuron (SMN) protein characterized by selective death of lower motor neurons.

To evaluate the efficiency of motor neuron transduction with an AAV9 variant (AAVhu68) using this approach, we treated three juvenile nonhuman primates (NHPs; age 14 months) and three piglets (age 7-30 days) with an intravenous injection of an AAVhu68 vector carrying a human SMN transgene at a dose similar to that employed in the SMA clinical trial. Administration of 2x1014 genome copies per kilogram body weight resulted in widespread transduction of spinal motor neurons in both species.

However, severe toxicity occurred in both NHPs and piglets. All three NHPs exhibited marked transaminase elevations. In two NHPs the transaminase elevations resolved without clinical sequelae, while one NHP developed acute liver failure and shock and was euthanized 4 days after vector injection. Degeneration of dorsal root ganglia (DRG) sensory neurons was also observed, although NHPs exhibited no clinically apparent sensory deficits. There was no correlation between clinical findings and T-cell responses to the vector capsid or transgene product in NHPs. Piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection all three animals exhibited proprioceptive deficits and ataxia which profoundly impaired ambulation and necessitated euthanasia. These clinical findings correlated with more severe DRG sensory neuron lesions than those observed in NHPs. The liver and sensory neuron findings appear to be a direct consequence of AAV transduction independent of an immune response to the capsid or transgene product.

The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of intravenous delivery of AAV vectors at high doses irrespective of the capsid serotype or transgene. Preclinical and clinical studies involving high systemic doses of AAV vectors should include careful monitoring for similar toxicities.