Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model

Keeler, Allison M.; Zieger, Marina; Semple, Carson; Pucci, Logan; Veinbachs, Alessandra; Brown, Robert H.; Mueller, Christian; ElMallah, Mai K.

doi:10.1016/j.omtm.2019.12.007

Cited by 23 publications

(23 citation statements)

References 49 publications

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“…Intralingual vector delivery effectively drives gene and protein expression in the tongue [32,[45][46][47] and can reverse tongue muscle histopathology in neuromuscular disease [45][46][47]. Pompe disease is a neuromuscular disorder associated with mutations in a single gene (acid alpha glucosidase or GAA), macroglossia, dysphagia, and dysarthria [48].…”

Section: Targeting the Tongue Via Intralingual Viral Deliverymentioning

confidence: 99%

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

et al. 2021

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Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. First, correcting tongue myofiber and/or hypoglossal (XII) motoneuron pathology in genetic neuromuscular disorders may be readily achieved by intralingual delivery of viral vectors. The retrograde movement of viral vectors such as adeno-associated virus (AAV) enables targeted distribution to XII motoneurons via intralingual viral delivery. Second, conditions with impaired or reduced tongue muscle activation can potentially be treated using viral-driven chemo- or optogenetic approaches to activate or inhibit XII motoneurons and/or tongue myofibers. Further considerations that are highly relevant to lingual gene therapy include (1) the diversity of the motoneurons which control the tongue, (2) the patterns of XII nerve branching, and (3) the complexity of tongue muscle anatomy and biomechanics. Preclinical studies show considerable promise for lingual directed gene therapy in neuromuscular disease, but the potential of such approaches is largely untapped.

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Section: Targeting the Tongue Via Intralingual Viral Deliverymentioning

confidence: 99%

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

et al. 2021

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“…Furthermore, treatment delayed weight loss and limb weakness. Despite the therapy succeeding in improving breathing and survival, it failed to amend the restrictive lung phenotype [ 110 ]. Although we consider the AAV with artificial miRNAs targeting SOD1 systems to show promising outcomes, we need to keep track of it for the next few years.…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders

Paul

Bravo-Vázquez

Uribe

et al. 2020

Cells

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MicroRNAs (miRNAs) are a key gene regulator and play essential roles in several biological and pathological mechanisms in the human system. In recent years, plenty of miRNAs have been identified to be involved in the development of neurodegenerative disorders (NDDs), thus making them an attractive option for therapeutic approaches. Hence, in this review, we provide an overview of the current research of miRNA-based therapeutics for a selected set of NDDs, either for their high prevalence or lethality, such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, Friedreich’s Ataxia, Spinal Muscular Atrophy, and Frontotemporal Dementia. We also discuss the relevant delivery techniques, pertinent outcomes, their limitations, and their potential to become a new generation of human therapeutic drugs in the near future.

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“…Indeed, differences between fast and slow IT injection of viral vector in SOD1-G93A mice were analysed and it was demonstrated that the slower one enhances transduction of spinal cord and therapeutic efficacy [ 85 ]. Alternative delivery routes of administration are also investigated, such as a combination of intralingual and intrapleural injections [ 86 ].…”

Section: Aav-mediated Silencing Approaches For Fals (Sod1 and C9orf72mentioning

confidence: 99%

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Cappella

Pradat

Querin

et al. 2020

Journal of Neuromuscular Diseases

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Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes on-going clinical trials in which antisense oligonucleotides are used in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

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Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model

Cited by 23 publications

References 49 publications

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

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