Altered retinal vasculature is a biomarker of disease in Spinal Muscular Atrophy in mouse models and human patients

Spinal Muscular Atrophy (SMA) is a childhood form of motor neurone disease; frequently fatal before 3 years of age if left untreated. This inherited condition preferentially targets motor neurones, leading to predicted pathologies of debilitating muscle wasting and death from respiratory failure. However, it has become clear that depletion of the cell- ubiquitous SMN protein, which underlies the disease, also results in less aggressive pathologies in many other systems. There are now three different therapies available to patients, but only one targets systems with the central nervous system. This project set out to define an accessible biomarker of vascular dysfunction in mouse models and patients. The retina is a readily accessible vas-cular bed, both in terms of quantification in animal models and visu-alisation in patients. We initially quantified the form and extent of the primary retinal vasculature in the ‘Taiwanese’ model of severe SMA. These mice survive for up to 10 days, and the retinal vascu-lature develops over the same period. It was immediately apparent that the retinal vasculature was normal at birth in SMA mice, but then failed to continue the normal centripetal pattern of outgrowth towards the periphery of the retina. By postnatal day 8 (PND8) SMA retinas showed significantly depleted outgrowth, branching and density. One treatment for SMA is systemic injection of antisense (ASO) technology at birth, which results in increased survival (as previously shown) and significantly, normalised retinal vasculature by PND 20. We next used retinal imaging to analyse retinal vasculature in patients. We chose to survey less severe, slightly older children, as the youngest are unable to maintain sufficient attention for the protocol. Importantly, these patients showed very similar defects to the mouse model, in terms of branching and coverage. These data show that significant vascular defects are present, even in less severe SMA patients that can be monitored in the clinic. This may prove to be a novel, useful biomarker for systemically active therapies, including antisense and small molecules. Animal experiments were performed under the Home Office project licence PPL 70/8389. Ethical approval for patient monitoring was granted by the Great Ormond St Hospital ethical review board