TitleCell-penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model.
Publication TypeJournal Article
Year of Publication2021
AuthorsBersani, M, Rizzuti, M, Pagliari, E, Garbellini, M, Saccomanno, D, Moulton, HM, Bresolin, N, Comi, GP, Corti, S, Nizzardo, M
JournalMol Ther
Date Published2021 Nov 19

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.

Alternate JournalMol Ther
PubMed ID34808387