Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future

Piguet, Françoise; Alves, Sandro; Cartier, Nathalie

doi:10.1089/hum.2017.160

Cited by 93 publications

(80 citation statements)

References 141 publications

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“…In addition to choice of capsid for safest and most disease-relevant spatial and temporal requirement for transgene expression, alterations to the transgene-coding region and regulatory elements are also common. Most clinical studies currently use high-expressing ubiquitous promoters such as variants of the human cytomegalovirus (CMV) or chicken beta-actin (CBA) promoters with CMV enhancer (CAG) [70]. Variations of this promoter have been characterized extensively and show robust expression throughout neuronal cell types in the CNS [71].…”

Section: Choice Of Aav Capsid Serotype and Promotermentioning

confidence: 99%

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

Pérez

Shutterly²,

Chan

et al. 2020

Brain Sciences

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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.

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Section: Choice Of Aav Capsid Serotype and Promotermentioning

confidence: 99%

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

Pérez

Shutterly²,

Chan

et al. 2020

Brain Sciences

View full text Add to dashboard Cite

show abstract

“…The recent approval of human AAV vector use in Europe and the USA has led to an array of gene therapy attempts in various clinical trials (Piguet et al, 2017;Axelsen and Woldbye, 2018;Hitti et al, 2019). The genetic approaches taken for PD treatment are largely neuro-regenerative in nature, and they are directed to halt neuronal cell death.…”

Section: Viral Vectorsmentioning

confidence: 99%

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Iarkov

Barreto

Grizzell

et al. 2020

Front. Aging Neurosci.

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Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

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“…The ability to target specific brain regions for gene therapy, as shown here, may prevent spreading Lewy pathology following α‐syn knockdown and also rescue failing neurons when combined with regeneration strategies using growth factors. Previous phases I and II clinical trials used viral vectors to express growth factors (neurturin, Glial cell line‐Derived Neurotrophic Factor (GDNF)) or increase dopamine biosynthesis (TH, aromatic L‐amino‐acid decarboxylase, and Guanosine triphosphate (GTP) cyclohydrolase‐1) . These trials involved small numbers of patients with fairly advanced disease and revealed only transient or modest benefits despite long‐lasting and well‐tolerated transgene expression.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive delivery of an α‐synuclein gene silencing vector with magnetic resonance–guided focused ultrasound

et al. 2018

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Background: The characteristic progression of Lewy pathology in Parkinson’s disease likely involves intercellular exchange and accumulation of misfolded α-synuclein amplified by a prion-like self-templating mechanism. Silencing of the α-synuclein gene could provide long-lasting disease modifying benefits by reducing the requisite substrate for the spreading aggregation. Objectives: Due to poor penetration of viral vectors across the blood-brain barrier, gene therapy for central nervous system disorders requires direct injections into affected brain regions, and invasiveness is further increased by the need for bilateral delivery to multiple brain regions. Here we test a non-invasive approach by combining low intensity MR-guided focused ultrasound and intravenous microbubbles that can transiently increase the access of brain impermeant therapeutic macromolecules to targeted brain regions. Methods: Transgenic mice expressing human α-synuclein were subjected to MR-guided focused ultrasound targeted to four brain regions (hippocampus, substantia nigra, olfactory bulb, and dorsal motor nucleus) in tandem with intravenous microbubbles and an adeno-associated virus serotype 9 vector bearing a short hairpin RNA sequence targeting the α-synuclein gene. Results: One month following treatment, α-synuclein immunoreactivity was decreased in targeted brain regions, whereas other neuronal markers such as synaptophysin or tyrosine hydroxylase were unchanged, and cell death and glial activation remained at basal levels. Conclusions: These results demonstrate that MR-guided focused ultrasound can effectively, non-invasively, and simultaneously deliver viral vectors targeting α-synuclein to multiple brain areas. Importantly, this approach may be useful to alter the progression of Lewy pathology along selected neuronal pathways, particularly as prodromal PD markers improve early diagnoses.

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Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future

Cited by 93 publications

References 141 publications

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

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

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Noninvasive delivery of an α‐synuclein gene silencing vector with magnetic resonance–guided focused ultrasound

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