AAV9 gene therapy optimization for SMARD1/CMT2S - safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model

Sep 29, 2026

Uploaded by Mary Man

Mutations in IGHMBP2 cause the rare, infantile, fatal motor neuron disease SMARD1 and the milder Charcot-Marie-Tooth disease type 2S (CMT2S). This study compares two optimized AAV9-IGHMBP2 vectors using either a Chicken β-Actin promoter (CBA) or a truncated MeCP2 promoter (P546) delivered intracerebroventricularly in a SMARD1 mouse model. Outcomes include survival, histopathology, and molecular readouts, including RNA sequencing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

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Abstract

Background

Methods

Results

Conclusion

Introduction

Pagliari et al. Journal of Biomedical Science (2026) 33:1 [https://doi.org/10.1186/s12929-025-01204-z](https://doi.org/10.1186/s12929-025-01204-z) RESEARCH Open Access AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model Elisa Pagliari 1, Alessia Anastasia2, Floriana Bellandi 1, Manuela Garbellini2, Jessica Ongaro2, MichelaTaiana1, Giacomo P. Comi 1, Linda Ottoboni1, Julieth Andrea Sierra‑Delgado3,4, Shibi Likhite3, Kathrin C. Meyer3,5, Monica Nizzardo2† and Stefania P. Corti 1,2,6*† Abstract Background Mutations in the Immunoglobulin Mu DNA Binding Protein 2 (IGHMBP2) gene cause Spinal Muscular Atro‑ phy with Respiratory Distress type 1 (SMARD1), a rare, infantile, and fatal motor neuron disease, as well as the milder Charcot‑Marie‑Tooth disease type 2S (CMT2S) . Gene therapy has emerged as a promising approach to correcting IGHMBP2 loss in SMARD1 models, but critical challenges remain. Methods In this study, we compared the efficacy of two novel, optimized adeno‑associated virus 9 (AAV9)‑IGHMBP2 vectors, utilizing either the Chicken β‑Actin (CBA) or a truncated form of the methyl‑CpG‑binding protein 2 (MeCP2) promoter (P546), in the SMARD1 murine model via intracerebroventricular delivery. Treated mice survival, histopatho‑ logical and molecular profile were analyzed. Results Corroborating previous findings, both constructs effectively rescued the pathological phenotype, signifi‑ cantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions. Notably, histopathological and RNA sequencing analyses revealed, for the first time, inflammatory marker alterations in the SMARD1 spinal cord, which resolved following treatment. A comparative analysis of the two vectors demonstrated superior long‑term efficacy of the P546‑promoter construct. Conclusion ICV gene therapy approach can effectively rescue SMARD1 pathological hallmarks, including astrogliosisand microgliosis. Moreover, P546‑promoter construct is superior in terms of safety profile and long‑term therapeutic efficacy. Keywords Motor neuron diseases, Adeno‑associated virus, Gene therapy, Viral vectors †Monica Nizzardo and Stefania P. Corti have contributed equally to the work. *Correspondence: Stefania P. Corti [stefania.corti@unimi.it](stefania.corti@unimi.it) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[http://creativeco](http://creativeco)[mmons.org/publicdomain/zero/1.0/](mmons.org/publicdomain/zero/1.0/)) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pagliari et al. Journal of Biomedical Science (2026) 33:1 Page 2 of 15 Graphical abstract Introduction Spinal Muscular Atrophy with Respiratory Distress typ

FAQs

What is the study testing in SMARD1 models?

The study compares two optimized AAV9-IGHMBP2 vectors with different promoters (CBA vs P546) delivered intracerebroventricularly in a SMARD1 murine model.

How were outcomes evaluated?

Treated-mouse survival was assessed, along with histopathological and molecular profiling, including RNA sequencing to identify changes in inflammatory markers.

Which vector showed better long-term performance and safety?

Both constructs improved survival, body weight, and motor function, but the P546-promoter construct demonstrated superior long-term efficacy and a better safety profile.

Sep 29, 2026

Uploaded by Mary Man