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)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.

Cell-penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model / M. Bersani, M. Rizzuti, E. Pagliari, M. Garbellini, D. Saccomanno, H.M. Moulton, N. Bresolin, G.P. Comi, S. Corti, M. Nizzardo. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - (2021), pp. 1-12. [Epub ahead of print] [10.1016/j.ymthe.2021.11.012]

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

M. Bersani
Primo
;
M. Rizzuti
Secondo
;
E. Pagliari;N. Bresolin;G.P. Comi;S. Corti
Penultimo
;
M. Nizzardo
Ultimo
2021

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)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.
antisense oligonucleotides; cell-penetrating peptides; spinal muscular atrophy; symptomatic treatment; systemic treatment;
Settore MED/26 - Neurologia
19-nov-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/890272
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