Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Figures

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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).…

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  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.