Abstract Details

Title Rescue of the Spinal Muscular Atrophy Phenotype in Mouse by Unmodified and Octa-Guanidine-Conjugated Morpholino Oligomers

Topic Anterior Horn

Presentation(s) P03 - (-)

Poster/Presentation
Number 044

Objective

Background BACKGROUND: SMA is a genetic motor neuron disease leading to infant mortality without effective treatment. SMA is caused by mutations in the SMN1 gene that results in a deficiency of SMN protein. It has been recently described the use of antisense oligonucleotides (ASOs) and morpholino (MO) to redirect the splicing of a paralogous gene, SMN2, to increase the production of functional SMN protein showing promising results in mouse models of SMA.

Design/Methods DESIGN/METHODS: We have designed a 25 bp MO against ISS-N1 [HSMN2Ex7D(-10,-34)] both as bare morpholino and with an octa-guanidine modification (vivo MO). We administered an intracerebroventricular injection of MO-10-34, bare or vivo MO, on P0 and/or subcutaneous on two separate days at P0 and P3 (two doses) into SMA ?7 mice. After treatment we analyzed SMN levels, SMA survival and phenotype modifications.

Results RESULTS: Bare and vivo MO injected rescued transgenic mice in a dose dependent manner (survival: 13 days to >100 days). Combined local and systemic treatments were superior respect to only one of these two conditions. MO-10-34 promoted the exon 7 inclusion and increased the SMN levels in the CNS and other organs and increased motor neuron number in the spinal cord which led to improvements in muscle physiology and in neuromuscular function. At the same concentration (5 nMoles) the treatment with MO-10-34 showed superior results respect to previously described sequences (MO-10-29 and ASO-10-27).

Conclusions CONCLUSIONS: The combined local and systemic administration of MO into SMA ?7 mice SMA effectively increases full-length SMN expression, leading to robust neuromuscular improvement and survival rescue. These results demonstrate that MO therapy is efficacious and represents a potential clinically meaningful tool for SMA therapy.

Authors/Disclosures
Stefania Corti, MD, PhD (Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico) PRESENTER	Dr. Corti has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Corti has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Corti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Nizar Souayah, MD, FAAN (NJMS)	Dr. Souayah has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda. Dr. Souayah has received publishing royalties from a publication relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Francesca Magri (University of Milan; Department of Neurology)	No disclosure on file
Nereo Bresolin, DR	No disclosure on file
	No disclosure on file

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