Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 22;10(2):119.
doi: 10.3390/brainsci10020119.

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

Barbara A Perez  1   2 , Alison Shutterly  3 , Ying Kai Chan  4   5 , Barry J Byrne  1 , Manuela Corti  1
Affiliations
Review

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

Barbara A Perez et al. Brain Sci. .

Abstract

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.

Keywords: AAV; gene therapy; immunosuppression; neurodegeneration; neuroinflammation.

PubMed Disclaimer

Conflict of interest statement

M.C. and B.J.B. are co-founders of AavantiBio, Inc. Y.K.C. is currently an employee of Ally Therapeutics.

Figures

Figure 1
Figure 1
Comparison of central nervous system (CNS)-directed dosing strategies. (a) Schematic diagram of relative location of cerebrospinal fluid (CSF)-targeting injections. (b) Table of pros and cons between common routes of CSF delivery.
Figure 2
Figure 2
Schematic overview of possible strategies to mitigate immune responses at various stages during gene therapy. (a) Pre-dosing considerations include vector design and treatment strategies to prepare the immune system for adeno-associated virus (AAV) exposure. (b) During dosing of the vector, the route of administration is selected in consideration of disease-relevant target tissues as to minimize toxicities from transgene overexpression or transgene expression in non-target tissues. (c) Post-dosing considerations include selection of immune management strategies that protect trangene expression and neural tissue and decrease neuroinflammation. .
See this image and copyright information in PMC

References

    1. Corti M., Norman S., Coleman K., Liberati C., Elder M., Escolar M., Clement N., Clever B., Byrne B., Gao G. Immune Blockade in CNS Gene Therapy Improves Safety and Clinical Outcome. Volume 26. Cell Press; Cambridge, MA, USA: 2018. p. 32. Molecular Therapy.
    1. Nair J., Freeman D., Jr., Davis I., McParland T., Pope M., Perez B., Rodriguez-Lebron E., Coleman K., Subramony S., Byrne B., et al. AAV9 Biodistribution with Different Routes of CNS Administration in Rodents. Volume 27. Cell Press; Cambridge, MA, USA: 2019. p. 259. Molecular Therapy.
    1. Perez B.A., Coleman K.E., Wichman M.B., Futch K.N., Mandolini K.E., Cravey L.D., Nair J., Cloutier D.A., Lynch D., Byrne B.J., et al. Management of Preexisting Immunity to AAV9 in Friedreich’s Ataxia. Volume 27. Cell Press; Cambridge, MA, USA: 2019. p. 140. Molecular Therapy.
    1. Perdomini M., Belbellaa B., Monassier L., Reutenauer L., Messaddeq N., Cartier N., Crystal R.G., Aubourg P., Puccio H. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat. Med. 2014;20:542–547. doi: 10.1038/nm.3510. - DOI - PubMed
    1. Mendell J.R., Al-Zaidy S., Shell R., Arnold W.D., Rodino-Klapac L.R., Prior T.W., Lowes L., Alfano L., Berry K., Church K., et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N. Engl. J. Med. 2017;377:1713–1722. doi: 10.1056/NEJMoa1706198. - DOI - PubMed