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Review
. 2022 Nov 30;12(12):1979.
doi: 10.3390/jpm12121979.

Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders

Cintia Gomez Limia  1 , Megan Baird  1   2 , Maura Schwartz  1   2 , Smita Saxena  3 , Kathrin Meyer  1   2   4 , Nicolas Wein  1   2   4
Affiliations
Review

Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders

Cintia Gomez Limia et al. J Pers Med. .

Abstract

Neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD) and Parkinson's Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NMDs) are a group of diseases in which patients show primary progressive muscle weaknesses, including Duchenne Muscular Dystrophy (DMD), Pompe disease, and Spinal Muscular Atrophy (SMA). NDDs and NMDs typically have a genetic component, which affects the physiological functioning of critical cellular processes, leading to pathogenesis. Currently, there is no cure or efficient treatment for most of these diseases. More than 200 clinical trials have been completed or are currently underway in order to establish safety, tolerability, and efficacy of promising gene therapy approaches. Thus, gene therapy-based therapeutics, including viral or non-viral delivery, are very appealing for the treatment of NDDs and NMDs. In particular, adeno-associated viral vectors (AAV) are an attractive option for gene therapy for NDDs and NMDs. However, limitations have been identified after systemic delivery, including the suboptimal capacity of these therapies to traverse the blood-brain barrier (BBB), degradation of the particles during the delivery, high reactivity of the patient's immune system during the treatment, and the potential need for redosing. To circumvent these limitations, several preclinical and clinical studies have suggested intrathecal (IT) delivery to target the CNS and peripheral organs via cerebrospinal fluid (CSF). CSF administration can vastly improve the delivery of small molecules and drugs to the brain and spinal cord as compared to systemic delivery. Here, we review AAV biology and vector design elements, different therapeutic routes of administration, and highlight CSF delivery as an attractive route of administration. We discuss the different aspects of neuromuscular and neurodegenerative diseases, such as pathogenesis, the landscape of mutations, and the biological processes associated with the disease. We also describe the hallmarks of NDDs and NMDs as well as discuss current therapeutic approaches and clinical progress in viral and non-viral gene therapy and enzyme replacement strategies for those diseases.

Keywords: CSF delivery; gene therapies; molecular biology; neurodegenerative diseases; neuromuscular diseases; therapeutic strategies.

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Conflict of interest statement

K.M received funding from Batten Disease Gene Therapy licensed to Amicus, K.M is consulting, Scientific advisor for Alcyone Therapeutic. N.W. is consulting and scientific advisor for Alcyone Therapeutic.

Figures

Figure 1
Figure 1
Recombinant AAVs are used for gene therapy. (A) The wild-type AAV consists of an icosahedral capsid and a viral DNA genome which includes the viral rep and cap genes. Rep gene encodes the proteins Rep78, 68, 52, and 40 under the promoter p5 or p19. Cap genes encode the proteins VP1, VP2, and VP3 under the promoter p40; both viral genes are flanked between two palindromic inverted-terminal repeats (ITRs). (B) Recombinant AAV (rAAV) consists of a capsid that contains the construct of interest. The construct plasmid encodes the transgene under a specific promotor and is flanked between two ITRs. (C) rAAV production is performed by co-transfection of two packaging plasmids and the construct plasmid (pAAV-Transgene) using host cells (e.g., HEK293). One packing plasmid encodes the rep and cap genes of a specific AAV serotype (pAAV-Rep/Cap) and the second plasmid is called helper (pAd-Helper), which expresses adenovirus helper genes (E2a, E4, VA). The transgene packaging capacity of a ssAAV is 4.4–4.7 kb.
Figure 2
Figure 2
Normal human CSF circulation and types of CSF injections. CSF is secreted by the choroid plexus into the lateral, 3rd, and 4th ventricles. CSF then flows to the subarachnoid space in two directions. The first is towards the intracranial subarachnoid space surrounding the brain. The second is towards the spinal subarachnoid space in the spinal cord. After the CSF completes circulation in the spinal cord, it then flows back to the brain. CSF drains through arachnoid villi to the venous sinuses (superior sagittal sinus) and into venous blood. Black arrows indicate the normal circulation of CSF in humans The injection sites along the CNS are indicated from numbers 1 to 5. 1—Intrapharenchymal (IP) administration, 2—Intracerebroventricular (ICV) administration, 3—Intracisterna magna (ICM), 4—Intrathecal (IT) injection in the cervical region of the spinal cord, 5—Intrathecal (IT) injection in the lumbar region of the spinal cord.
Figure 3
Figure 3
Overview of the blood–brain barrier (BBB). The BBB is a critical component of the neurovascular unit (NVU), which contains neurons and interneurons, microglia, astrocytes (end feet), endothelial cells, and pericytes found around the brain capillaries. Microglial cells protect the brain from microorganisms by phagocytosis. Pericytes surrounded endothelial cells and contributed to the integrity of the BBB. A basement membrane is found between the astrocyte (end feet) and the pericytes. Endothelial cells (ECs), connected by tight junctions (TJs), also contain transporters and receptors. TJs regulate the transport of molecules and ions to the brain. ECs transport nutrients and regulatory molecules (influx/eflux) to the brain through passive or active mechanisms. Cell–cell interaction can regulate numerous functions in the brain, including those important for cerebral homeostasis.
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