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 used morpholino (MO) chemistry to conjugate antisense oligonucleotides 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.

Cell Penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model / E. Pagliari, M. Bersani, M. Rizzuti, A. Bordoni, D. Saccomanno, H.M. Moulton, N. Bresolin, G.P. Comi, S. Corti, M. Nizzardo. ((Intervento presentato al convegno Motor Neuron Diseases: understanding the pathogenetic mechanisms to develop therapies tenutosi a online nel 2020.

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

E. Pagliari;M. Bersani;M. Rizzuti;A. Bordoni;N. Bresolin;G.P. Comi;S. Corti;M. Nizzardo
2020

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 used morpholino (MO) chemistry to conjugate antisense oligonucleotides 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.
Settore MED/26 - Neurologia
Italian Society for Neuroscience
Cell Penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model / E. Pagliari, M. Bersani, M. Rizzuti, A. Bordoni, D. Saccomanno, H.M. Moulton, N. Bresolin, G.P. Comi, S. Corti, M. Nizzardo. ((Intervento presentato al convegno Motor Neuron Diseases: understanding the pathogenetic mechanisms to develop therapies tenutosi a online nel 2020.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/823172
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