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Cited by 32Virus-based gene therapy researchRNA Interference and Gene DeliveryNeurogenetic and Muscular Disorders Research

The DOI matches its Crossref record; 204 of the 205 references it cites were found in a registry or an index.

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

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Tosolini, Andrew P., Sleigh, James N.·2020·Frontiers in Molecular Neuroscience
DOI 10.3389/fnmol.2020.00129PMC PMC7379875
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Abstract

Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia. This route is minimally invasive and therefore clinically relevant for gene therapy targeting to peripheral nerve soma. For successful transgene expression, viruses administered into muscle must undergo a series of processes, including host cell interaction and internalization, intracellular sorting, long-range retrograde axonal transport, endosomal liberation, and nuclear import. In this review article, we outline key characteristics of major gene therapy viruses-adenovirus, adeno-associated virus (AAV), and lentivirus-and summarize the mechanisms regulating important steps in the virus journey from binding at peripheral nerve terminals to nuclear delivery. Additionally, we describe how neuropathology can negatively influence these pathways, and conclude by discussing opportunities to optimize the intramuscular administration route to maximize gene delivery and thus therapeutic potential.

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Crossref · 10.3389/fnmol.2020.00129

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Figure 1 The journey of gene therapy viruses from peripheral nerve terminals to the nucleus. Viruses used to deliver gene therapy must access cell nuclei to express their packaged genetic material. When administered into muscles for targeting of peripheral nerve somas, viruses such as adenovirus, adeno-associated virus (AAV) and lentivirus, undergo a series of processes that aid their transfer from the periphery to CNS (depicted here using AAV as an example). (A) First, the virus interacts with specific host cell surfaces. This entails primary receptor binding (e.g., glycans) followed by internalization, which is often mediated, at least in part, by a secondary receptor (e.g., AAV receptor, AAVR or fibroblast growth factor receptor, FGFR). Internalization at nerve terminals is regulated by a variety of endocytic pathways. Post-internalisation, viruses hijack the Rab GTPase-mediated endosomal sorting system, transitioning through Rab5-positive early endosomes to non-acidic Rab7-positive late endosomes. (B) Virus-containing Rab7-positive signaling endosomes are actively transported along microtubules by cytoplasmic dynein-dynactin complexes towards nerve cell bodies (i.e., retrogradely). (C) At the neuronal soma, viruses escape endosomes and are processed, sometimes through the Golgi apparatus, before entry into the nucleus (e.g., via the nuclear pore complex), where the virus can begin to drive transgene expression.
Figure 1 The journey of gene therapy viruses from peripheral nerve terminals to the nucleus. Viruses used to deliver gene therapy must access cell nuclei to express their packaged genetic material. When administered into muscles for targeting of peripheral nerve somas, viruses such as adenovirus, adeno-associated virus (AAV) and lentivirus, undergo a series of processes that aid their transfer from the periphery to CNS (depicted here using AAV as an example). (A) First, the virus interacts with specific host cell surfaces. This entails primary receptor binding (e.g., glycans) followed by internalization, which is often mediated, at least in part, by a secondary receptor (e.g., AAV receptor, AAVR or fibroblast growth factor receptor, FGFR). Internalization at nerve terminals is regulated by a variety of endocytic pathways. Post-internalisation, viruses hijack the Rab GTPase-mediated endosomal sorting system, transitioning through Rab5-positive early endosomes to non-acidic Rab7-positive late endosomes. (B) Virus-containing Rab7-positive signaling endosomes are actively transported along microtubules by cytoplasmic dynein-dynactin complexes towards nerve cell bodies (i.e., retrogradely). (C) At the neuronal soma, viruses escape endosomes and are processed, sometimes through the Golgi apparatus, before entry into the nucleus (e.g., via the nuclear pore complex), where the virus can begin to drive transgene expression.CC BY · PubMed Central
Figure 2 Neuropathological events impair the viral transduction of peripheral neurons. Several general and virus-specific pathological events caused by neurological disease diminish the effectiveness of gene therapy delivery to the nervous system via muscle. (A) Loss of motor and sensory nerve endings due to neurodegeneration will restrict nerve-muscle connections and the frequency of virus-nerve interaction. (B) Alterations in the expression or availability of certain primary or secondary receptors will affect virus attraction and binding. Deficits in endocytosis, as seen in spinal muscular atrophy (SMA), or impaired endosomal sorting, as identified in amyotrophic lateral sclerosis (ALS) and some forms of Charcot-Marie Tooth disease (CMT), could reduce virus uptake into peripheral nerve terminals. Defects in Golgi processing and nuclear import may also decrease viral transduction (not depicted). (C) A variety of impairments affecting axonal transport machinery (e.g., microtubule dysfunction) are known to cause defects in cargo trafficking (e.g., slowed transport or reduced quantity/flux), which will limit viral delivery.
Figure 2 Neuropathological events impair the viral transduction of peripheral neurons. Several general and virus-specific pathological events caused by neurological disease diminish the effectiveness of gene therapy delivery to the nervous system via muscle. (A) Loss of motor and sensory nerve endings due to neurodegeneration will restrict nerve-muscle connections and the frequency of virus-nerve interaction. (B) Alterations in the expression or availability of certain primary or secondary receptors will affect virus attraction and binding. Deficits in endocytosis, as seen in spinal muscular atrophy (SMA), or impaired endosomal sorting, as identified in amyotrophic lateral sclerosis (ALS) and some forms of Charcot-Marie Tooth disease (CMT), could reduce virus uptake into peripheral nerve terminals. Defects in Golgi processing and nuclear import may also decrease viral transduction (not depicted). (C) A variety of impairments affecting axonal transport machinery (e.g., microtubule dysfunction) are known to cause defects in cargo trafficking (e.g., slowed transport or reduced quantity/flux), which will limit viral delivery.CC BY · PubMed Central

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Metadata

Authors
Tosolini, A. P., & Sleigh, J. N.
Affiliations
  • UCL Queen Square Institute of Neurology (GB)
  • UK Dementia Research Institute (GB)
Corresponding author
  • Tosolini, Andrew P.
  • Sleigh, James N.
ORCID
Venue
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Published
2020-07-17
Volume
13
Pages
129-129
ISSN
1662-5099 (ISSN-L)
DOI
10.3389/fnmol.2020.00129
PMC
PMC7379875
OpenAlex
W3043715250
Cited by
32
References
205
Citations by year
2026: 4 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 6
FWCI
2.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (107116/Z/15/Z)
  • Medical Research Council (MR/S006990/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
Keywords
intramuscular gene delivery, gene therapy vectors, retrograde axonal transport, peripheral nerve terminals, motor neurons, sensory neurons, adeno-associated virus, adenovirus, lentivirus, viral transduction, endosomal escape, nuclear import, neuropathology

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