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Cell-Penetrating Peptide-Conjugated Morpholino Rescues SMA in a Symptomatic Preclinical Model

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source: Molecular therapy : the journal of the American Society of Gene Therapy

year: 2021

authors: Bersani M,Rizzuti M,Pagliari E,Garbellini M,Saccomanno D,Moulton HM,Bresolin N,Comi GP,Corti S,Nizzardo M


Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. Recently approved SMA therapies have transformed a deadly disease into a survivable one, but these compounds show a wide spectrum of clinical response and effective rescue only in the early stages of the disease. Therefore, safe, symptomatic-suitable, non-invasive treatments with high clinical impact across different phenotypes are urgently needed. We conjugated antisense oligonucleotides with Morpholino (MO) chemistry, which increase SMN protein levels, to cell-penetrating peptides (CPPs) for better cellular distribution. Systemically administered MOs linked to r6 and (RXRRBR)XB peptides crossed the blood-brain barrier and increased SMN protein levels remarkably, causing striking improvement of survival, neuromuscular function, and neuropathology, even in symptomatic SMA animals. Our study demonstrates that MO-CPP conjugates can significantly expand the therapeutic window through minimally invasive systemic administration, opening the path for clinical applications of this strategy.

organization: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.

DOI: 10.1016/j.ymthe.2021.11.012

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