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Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases

1
Department of Pediatrics and Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA
2
Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
3
AavantiBio, Inc., Gainesville, FL 32601, USA
4
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
5
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Brain Sci. 2020, 10(2), 119; https://doi.org/10.3390/brainsci10020119
Received: 30 January 2020 / Revised: 17 February 2020 / Accepted: 20 February 2020 / Published: 22 February 2020
(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Diseases)
Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy. View Full-Text
Keywords: AAV; gene therapy; neurodegeneration; neuroinflammation; immunosuppression AAV; gene therapy; neurodegeneration; neuroinflammation; immunosuppression
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Perez, B.A.; Shutterly, A.; Chan, Y.K.; Byrne, B.J.; Corti, M. Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases. Brain Sci. 2020, 10, 119.

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