Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models.
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of Survival Motor Neuron-1 (SMN1). In all SMA patients, a nearly identical copy gene called SMN2 is present, which produces low levels of functional protein owing to an alternative splicing event. To prevent exon-skipping, we have targeted an intronic repressor, Element1 (E1), located upstream of SMN2 exon 7 using Morpholino-based antisense oligonucleotides (E1(MO)-ASOs). A single intracerebroventricular injection in the relatively severe mouse model of SMA (SMNΔ7 mouse model) elicited a robust induction of SMN protein, and mean life span was extended from an average survival of 13 to 54 days following a single dose, consistent with large weight gains and a correction of the neuronal pathology. Additionally, E1(MO)-ASO treatment in an intermediate SMA mouse (SMN(RT) mouse model) significantly extended life span by ∼700% and weight gain was comparable with the unaffected animals. While a number of experimental therapeutics have targeted the ISS-N1 element of SMN2 pre-mRNA, the development of E1 ASOs provides a new molecular target for SMA therapeutics that dramatically extends survival in two important pre-clinical models of disease.
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65211, USA, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Erkan Y
EY
Osman
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA, Genetics Area Program, Christopher S. Bond Life Sciences Center Room 403, University of Missouri, Columbia, MO 65211, USA and.
Madeline R
MR
Miller
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Kate L
KL
Robbins
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Abby M
AM
Lombardi
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Arleigh K
AK
Atkinson
College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Amanda J
AJ
Brehm
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65211, USA, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA, Genetics Area Program, Christopher S. Bond Life Sciences Center Room 403, University of Missouri, Columbia, MO 65211, USA and lorsonc@missouri.edu.
Christian L
CL
Lorson
D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007438:Introns; D051379:Mice; D060172:Morpholinos / Q000008:administration & dosage*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012045:Regulatory Sequences, Nucleic Acid; D015996:Survival Rate; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain
D060172:Morpholinos; C000597152:SMN2 protein, mouse; D055540:Survival of Motor Neuron 2 Protein