Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, resulting in deficiency of SMN protein. Most of the emerging therapies are based on redirecting the splicing of SMN2, the paralogous gene, to produce a functional SMN protein. In our laboratory, a specific sequence of the antisense oligonucleotide Morpholino (MO) against the ISS-N1 region of SMN2, the MO-10-34, has been successfully tested in pre-symptomatic SMA mice. To develop a functional treatment for symptomatic patients, cell-penetrating peptides (CPPs) can be conjugated to ASOs, allowing the crossing of the blood-brain barrier (BBB). This approach has been preliminarily explored with MO conjugated with four different peptides in pre-symptomatic mice, demonstrating the major efficacy of r6 and RXR, on which we focused further experiments. To verify the ability of MO-conjugated to CPPs to cross the BBB and ameliorate SMA mice phenotype and neuropathological features compared to unconjugated-MO, two group of symptomatic mice animals were treated at p5 with r6-MO, RXR-MO and unconjugated MO by intraperitoneal injection. The first group was monitored for survival and phenotypical behaviour. The second group was sacrificed at p30, spinal cord and intercostal muscles were harvested and analysed by immunofluorescence for the presence of motor neurons and innervated neuro muscular junctions. Our results confirm that both CPPs-conjugated MOs ameliorate the biodistribution of the MO into the CNS increasing significantly phenotypical and neuropathological features compared to unconjugated MO.

CPPs-conjugated antisense nucleotides : a new therapeutic strategy for Spinal Muscular Atrophy symptomatic patients / E. Pagliari, M. Bersani, M. Rizzuti, A. Bordoni, D. Saccomanno, N. Bresolin, G. Comi, S. Corti, M. Nizzardo. ((Intervento presentato al convegno Congresso Congiunto AIM-ASNP tenutosi a online nel 2020.

CPPs-conjugated antisense nucleotides : a new therapeutic strategy for Spinal Muscular Atrophy symptomatic patients

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

Abstract

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, resulting in deficiency of SMN protein. Most of the emerging therapies are based on redirecting the splicing of SMN2, the paralogous gene, to produce a functional SMN protein. In our laboratory, a specific sequence of the antisense oligonucleotide Morpholino (MO) against the ISS-N1 region of SMN2, the MO-10-34, has been successfully tested in pre-symptomatic SMA mice. To develop a functional treatment for symptomatic patients, cell-penetrating peptides (CPPs) can be conjugated to ASOs, allowing the crossing of the blood-brain barrier (BBB). This approach has been preliminarily explored with MO conjugated with four different peptides in pre-symptomatic mice, demonstrating the major efficacy of r6 and RXR, on which we focused further experiments. To verify the ability of MO-conjugated to CPPs to cross the BBB and ameliorate SMA mice phenotype and neuropathological features compared to unconjugated-MO, two group of symptomatic mice animals were treated at p5 with r6-MO, RXR-MO and unconjugated MO by intraperitoneal injection. The first group was monitored for survival and phenotypical behaviour. The second group was sacrificed at p30, spinal cord and intercostal muscles were harvested and analysed by immunofluorescence for the presence of motor neurons and innervated neuro muscular junctions. Our results confirm that both CPPs-conjugated MOs ameliorate the biodistribution of the MO into the CNS increasing significantly phenotypical and neuropathological features compared to unconjugated MO.
SMA; morpholino; CPPs
Settore MED/26 - Neurologia
Associazione Italiana di Miologia
Associazione Italiana per lo studio del Sistema Nervoso Periferico
CPPs-conjugated antisense nucleotides : a new therapeutic strategy for Spinal Muscular Atrophy symptomatic patients / E. Pagliari, M. Bersani, M. Rizzuti, A. Bordoni, D. Saccomanno, N. Bresolin, G. Comi, S. Corti, M. Nizzardo. ((Intervento presentato al convegno Congresso Congiunto AIM-ASNP 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/2434/823192
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