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.
Highlights
In recent years, adeno-associated virus (AAV)-mediated gene therapies have gained clinical interest for treating a wide variety of neurodegenerative and neuromuscular diseases including spinal muscular atrophy (SMA) (NCT02122952; NCT03306277, NCT03381729), Canavan disease (CD) [1], Alzheimer’s disease (AD) (NCT03634007), and Friedreich’s ataxia (FA) [2,3,4]
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
The increased interest in AAV-mediated gene therapies has led to multiple successful clinical trials, with the first approved gene therapy product for a neurodegenerative disease, SMA, in 2019 [5]
Summary
Adeno-associated virus (AAV)-mediated gene therapies have gained clinical interest for treating a wide variety of neurodegenerative and neuromuscular diseases including spinal muscular atrophy (SMA) (NCT02122952; NCT03306277, NCT03381729), Canavan disease (CD) [1], Alzheimer’s disease (AD) (NCT03634007), and Friedreich’s ataxia (FA) [2,3,4]. Preclinical studies in large animal models detect AAV-related markers of neuroinflammation and CNS pathology even after CNS-specific delivery methods [20,21], suggesting that the issue of host immune responses to the vector is not exclusive to systemic dosing strategies While most of these reports show no phenotypic consequence of the pathology at the time points tested (typically 1–3 months post-dose), it is important to understand triggers (e.g., route of delivery, manufacturing impurities in vector material, transgene overexpression), mechanisms of the inflammation (e.g., infiltration of peripheral immune cells, immune reaction within the CNS, transgene-mediated neurotoxicity), and the long-term effects of neuroinflammation.
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