Evidence map›Paper›PMID 41486111›Full record

ArticleJournal of biomedical science2026

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

Elisa Pagliari, Alessia Anastasia, Floriana Bellandi, Manuela Garbellini, Jessica Ongaro, Michela Taiana, Giacomo P Comi, Linda Ottoboni, Julieth Andrea Sierra-Delgado, Shibi Likhite and 3 more

Abstract readComparative Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of biomedical science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. A class of deep intronicmedRxiv : the preprint server for health sciences · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Elisa PagliariDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Alessia AnastasiaNeurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Floriana BellandiDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Manuela GarbelliniNeurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Jessica OngaroNeurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Michela TaianaDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Giacomo P ComiDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Linda OttoboniDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Julieth Andrea Sierra-DelgadoCenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
Shibi LikhiteCenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
Kathrin C MeyerCenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
Monica Nizzardo *Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Stefania P Corti *Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. stefania.corti@unimi.it.

Funding

Fondazione Cariplo 2015-0776Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico PNRR-POC-2023-12377653Ministero della Salute PNC-E3-2022-23683266Ministero dell'Istruzione, dell'Università e della Ricerca Dipartimenti di Eccellenza Program 2023-2027
6 · The paper itself

Abstract

backgroundMutations in the Immunoglobulin Mu DNA Binding Protein 2 (IGHMBP2) gene cause Spinal Muscular Atrophy 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.

methodsIn 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, histopathological and molecular profile were analyzed.

resultsCorroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly 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.

conclusionICV gene therapy approach can effectively rescue SMARD1 pathological hallmarks, including astrogliosis and microgliosis. Moreover, P546-promoter construct is superior in terms of safety profile and long-term therapeutic efficacy.

Indexed as

Charcot-Marie-Tooth DiseaseDependovirusDNA-Binding ProteinsGenetic TherapyGenetic VectorsMuscular Atrophy, SpinalTranscription FactorsAnimalsDisease Models, AnimalHumansMiceRespiratory Distress Syndrome, NewbornDNA-Binding ProteinsTranscription FactorsAdeno-associated virusGene therapyMotor neuron diseasesViral vectors

Identifiers

PMID41486111
PMCPMC12765291

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.