AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice

• Published in: Molecular therapy Vol. 28; no. 8; pp. 1887 - 1901
• Main Authors: Besse, Aurore, Astord, Stephanie, Marais, Thibaut, Roda, Marianne, Giroux, Benoit, Lejeune, François-Xavier, Relaix, Frederic, Smeriglio, Piera, Barkats, Martine, Biferi, Maria Grazia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2020; Cell Press; American Society of Gene & Cell Therapy
• Subjects: AAV; gene therapy; Life Sciences; neurons; Original; peripheral organs; SMA; SMN; spinal muscular atrophy; synapsin promoter; ubiquitous promoter; synapsin promoter; ubiquitous promoter; SMN; SMA; AAV; gene therapy; peripheral organs; spinal muscular atrophy; neurons
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2020.05.011

Spinal muscular atrophy (SMA) is a neuromuscular disease mainly caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene and characterized by the degeneration of motor neurons and progressive muscle weakness. A viable therapeutic approach for SMA patients is a gene replacement strategy that restores functional SMN expression using adeno-associated virus serotype 9 (AAV9) vectors. Currently, systemic or intra-cerebrospinal fluid (CSF) delivery of AAV9-SMN is being explored in clinical trials. In this study, we show that the postnatal delivery of an AAV9 that expresses SMN under the control of the neuron-specific promoter synapsin selectively targets neurons without inducing re-expression in the peripheral organs of SMA mice. However, this approach is less efficient in restoring the survival and neuromuscular functions of SMA mice than the systemic or intra-CSF delivery of an AAV9 in which SMN is placed under the control of a ubiquitous promoter. This study suggests that further efforts are needed to understand the extent to which SMN is required in neurons and peripheral organs for a successful therapeutic effect. [Display omitted] Delivery of the SMN protein via adeno-associated viral vectors (AAVs) is approved for the treatment of spinal muscular atrophy (SMA). A novel AAV construction tested to selectively target neurons was unable to rescue a SMA mouse model. SMN replacement in both neurons and peripheral organs is thus necessary for SMA treatment.