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Cell-Penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model

Bersani M, Rizzuti M, Pagliari E, Garbellini M, Saccomanno D, Moulton HM, Bresolin N, Comi GP, Corti S, Nizzardo M
Molec Ther. 2021 Nov 19;S1525-0016(21)00583-9. doi: 10.1016/j.ymthe.2021.11.012
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, that increase SMN protein levels, to cell-penetrating peptides (CPPs) for better cellular distribution. Systemically administered MOs linked to r6 and (RXRRBR)2XB 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.
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