A paper describing preclinical work that was foundational for the gene therapy for spinal muscular atrophy now sold as Zolgensma has been retracted for data inaccuracies.
The article, “Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN,” was published in Nature Biotechnology in 2010. Its corresponding author, Brian Kaspar, was at The Ohio State University at the time. Kaspar went on to become the scientific founder and chief scientific officer of AveXis, which created Zolgensma and was acquired by Novartis in 2018 for $8.7 billion.
The paper has been cited 557 times, according to Clarivate’s Web of Science, and referenced in at least 59 patents, according to Altmetric.
According to the retraction notice, the authors contacted the journal last year about “inaccuracies” in the data. After the journal’s investigation, the editors decided to retract the article over the author’s objections. The notice explained:
The editors are retracting this article owing to issues that have come to our attention regarding the data reported in a key figure. In 2021, the authors alerted the journal to inaccuracies in Fig. 1e, a Kaplan–Meier curve representing the survival of spinal muscular atrophy mice that received either the scAAV9-SMN gene therapy or a control scAAV9-GFP vector. In 2022, the authors provided the original source data file for Fig. 1e, which confirmed multiple inaccuracies in the reported mouse lifespans and in the animal inclusions and exclusions. Notably, only one treated mouse, not the reported six mice, survived for more than 250 days. On the basis of reviewer and editorial assessment of the data, we are of the opinion that the extent of the inaccuracies in Fig. 1e and associated text undermines full confidence in the study.
The authors Kevin D Foust, Xueyong Wang, Vicki L McGovern, Lyndsey Braun, Adam K Bevan, Thanh T Le, Pablo R Morales, Mark M Rich, Arthur H M Burghes and Brian K Kaspar disagree with the retraction. Amanda M Haidet did not respond after several attempts were made to contact her.
Neither first author Foust nor Kaspar immediately responded to a LinkedIn message seeking comment on how they became aware of the inaccuracies.
Novartis, which markets the spinal muscular atrophy gene therapy Zolgensma, ousted Kaspar and his brother Allan from their jobs as scientific executives at AveXis in 2019, after the company discovered data manipulation in its application for FDA approval. That incident appears to be unrelated to the issues described in the retraction notice for the 2010 paper.
Tom Gillingwater, whose research lab at the University of Edinburgh focuses on developing therapies for spinal muscular atrophy, among other neurological diseases, tweeted his apparent astonishment at the retraction:
Gillingwater told us:
This paper represented one of a trio of ground-breaking studies published in 2010/2011 showing that restoring SMN protein levels using an AAV9-SMN1 gene therapy approach in SMA is safe and effective in vivo. As a result, it contributed significantly to the foundations for all subsequent pre-clinical and clinical work that led to the widespread approval of Zolgensma for the treatment of SMA. It is very disappointing to see the paper retracted for “multiple inaccuracies” (and I note that the authors don’t appear to agree with the decision: I hope they will be able/willing to make further details available to the research community in the future), but the fact that this approach was corroborated by other, independent pre-clinical studies, as well as substantial subsequent clinical trial data, minimises the knock-on consequences.
I don’t really have anything more specific to add, I’m afraid, apart from a hope that this doesn’t have a negative impact on the remarkable recent successes in the field of new therapeutics for SMA that have revolutionised treatment options for patients.
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