Editors' ChoiceGene Therapy

Baby steps in gene therapy

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Science Translational Medicine  24 Jun 2015:
Vol. 7, Issue 293, pp. 293ec108
DOI: 10.1126/scitranslmed.aac7151

Autosomal recessive disorders caused by missing or mutant proteins are low-hanging fruits for gene therapy. Indeed, replacing a defective gene with a healthy copy to obtain a replacement protein is possible, but the potential host immune response to “nonself” proteins poses a major challenge, especially in cases where the underlying mutation causes complete absence of the protein (rather than an inactive mutant). Now, Hinderer and co-workers capitalize on the normal process by which the immune system learns to distinguish self from nonself to circumvent this problem.

The authors studied the effects of gene therapy in a progressive neuropathic lysosomal storage disease, mucopolysaccharidosis, which is caused by deficiency in a secreted enzyme. They first taught the immune systems of dogs and macaques to recognize the missing protein by delivering a copy of the enzyme-encoding gene via adeno-associated virus type 8 (AAV8) into the liver. The neonates developed immunological tolerance to the secreted enzyme, which prepared them for a second treatment. The second administration used a different vector, AAV9, to deliver the same gene cargo, this time into the central nervous system (CNS). Naïve animals receiving only the second injection lost enzymatic activity owing to antibodies attacking the enzyme. Tolerant dogs and macaques, however, exhibited robust expression of the enzyme in their cerebrospinal fluid. Moreover, persistent enzyme levels in the CNS corrected the disease phenotype in sick dogs affected with mucopolysaccharidosis type 1.

If the same window of opportunity for teaching tolerance exists in humans, early tolerance development in neonates could open up new possibilities for gene therapy for autosomal recessive diseases. One caveat for this approach is the requirement for newborn screening to detect the genetic disorder. The good news for MPS-1 is that newborn screening is just being implemented in several states in the United States, creating opportunities to translate this approach by Hinderer et al. towards a first-in-human study.

C. Hinderer et al., Neonatal systemic AAV induces tolerance to CNS gene therapy in MPS I dogs and nonhuman primates. Mol. Ther. 10.1038/mt.2015.99 (2015). [Abstract]

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