Title | Cell-penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Bersani, M, Rizzuti, M, Pagliari, E, Garbellini, M, Saccomanno, D, Moulton, HM, Bresolin, N, Comi, GP, Corti, S, Nizzardo, M |
Journal | Mol Ther |
Date Published | 2021 Nov 19 |
ISSN | 1525-0024 |
Abstract | 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. |
DOI | 10.1016/j.ymthe.2021.11.012 |
Alternate Journal | Mol Ther |
PubMed ID | 34808387 |