Research ArticleGene Therapy

MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates

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Science Translational Medicine  11 Nov 2020:
Vol. 12, Issue 569, eaba9188
DOI: 10.1126/scitranslmed.aba9188

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Mitigating gene therapy toxicity

Gene therapy using adeno-associated viral (AAV) vectors has shown promising results for treating neurological conditions. However, studies in nonhuman primates (NHPs) have shown that gene therapy targeting the central nervous system can cause toxicity in dorsal root ganglia (DRGs) and consequent development of ataxia. Now, Hordeaux et al. took advantage of a microRNA present almost exclusively in DRG and showed that ablation of transgene expression specifically in DRGs reduced gene therapy–mediated toxicity in NHPs. The treatment did not affect transduction of the transgene in other cell populations. The results suggest that this approach might be useful for limiting DRG toxicity associated with CNS gene therapy.


Delivering adeno-associated virus (AAV) vectors into the central nervous system of nonhuman primates (NHPs) via the blood or cerebral spinal fluid is associated with dorsal root ganglion (DRG) toxicity. Conventional immune-suppression regimens do not prevent this toxicity, possibly because it may be caused by high transduction rates, which can, in turn, cause cellular stress due to an overabundance of the transgene product in target cells. To test this hypothesis and develop an approach to eliminate DRG toxicity, we exploited endogenous expression of microRNA (miR) 183 complex, which is largely restricted to DRG neurons, to specifically down-regulate transgene expression in these cells. We introduced sequence targets for miR183 into the vector genome within the 3′ untranslated region of the corresponding transgene messenger RNA and injected vectors into the cisterna magna of NHPs. Administration of unmodified AAV vectors resulted in robust transduction of target tissues and toxicity in DRG neurons. Consistent with the proposal that immune system activity does not mediate this neuronal toxicity, we found that steroid administration was ineffective in alleviating this pathology. However, including miR183 targets in the vectors reduced transgene expression in, and toxicity of, DRG neurons without affecting transduction elsewhere in the primate’s brain. This approach might be useful in reducing DRG toxicity and the associated morbidity and should facilitate the development of AAV-based gene therapies for many central nervous system diseases.

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