Microvasculopathy in SMA is driven by a reversible autonomous endothelial cell defect

Haiyan Zhou* (Corresponding Author), Ying Hong, Mariacristina Scoto, Alison Thomson, Emma Pead, Tom MacGillivray, Elena Hernandez Gerez, Francesco Catapano, Jinhong Meng, Qiang Zhang, Gillian Hunter, Hannah K. Shorrock, Thomas Ng, Abedallah Mahmod Shehda Hamida, Mathilde Sanson, Giovanni Baranello, Kevin Howell, Thomas H. Gillingwater, Paul Brogan, Dorothy Thompson* (Corresponding Author)Simon Parson*, Francesco Muntoni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by the deficiency of the ubiquitously expressed SMN protein. Here, we present a new retinal vascular defect in patients, recapitulated in SMA transgenic mice, driven by failure of angiogenesis and maturation of blood vessels. Importantly, the retinal vascular phenotype was rescued by early, systemic SMN restoration therapy in SMA mice. We also demonstrate in patients an unfavourable imbalance between endothelial injury
and repair, as indicated by blood cellular markers of increased endothelial injury and decreased endothelial repair. These markers of endothelial injury were significantly associated with disease severity and improved following SMN restoration treatment in Cultured endothelial cells from SMA patients. Finally, we demonstrated autonomous defects in angiogenesis and blood vessel formation, secondary to SMN deficiency in cultured human and mouse endothelial cells, as the underlying cellular mechanism of microvascular pathology. Our cellular and vascular biomarkers findings strongly indicate microvasculopathy as a novel and fundamental feature of SMA. Our finding provides mechanistic insights into previously described SMA microvascular complications, which may contribute to the thrombotic microangiopathy complications following AAV gene therapy, and highlight the novel functional role of SMN in the periphery.
Original languageEnglish
Article numbere153430
JournalJournal of Clinical Investigation
Issue number21
Early online date13 Sep 2022
Publication statusPublished - 1 Nov 2022


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