Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
ABSTRACT Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2'-O-2-methoxyethyl-modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system-directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic.
Neurobiology of Disease 05/1996; 3(2):97-110. · 5.40 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Spinal muscular atrophy is an autosomal recessive motor neuron disease that is the leading inherited cause of infant and early childhood mortality. Spinal muscular atrophy is caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1), but all patients retain a centromeric copy of the gene, SMN2. SMN2 produces reduced amounts of full-length SMN mRNA, and spinal muscular atrophy likely results from insufficient levels of SMN protein in motor neurons. The SMN protein plays a well-established role in assembly of the spliceosome and may also mediate mRNA trafficking in the axon and nerve terminus of neurons. In patients, spinal muscular atrophy disease severity correlates inversely with increased SMN2 gene copy number and, in transgenic mice lacking endogenous SMN, increasing SMN2 gene copy number from two to eight prevents the SMA disease phenotype. These observations suggest that increasing SMN expression levels may be beneficial to SMA patients. Currently pursued therapeutic strategies for SMA include induction of SMN2 gene expression, modulation of splicing of SMN2-derived transcripts, stabilization of SMN protein, neuroprotection of SMN deficit neurons, and SMN1 gene replacement. Early clinical trials of candidate therapeutics are now ongoing in SMA patients. Clinical trials in this disease present a unique set of challenges, including the development of meaningful outcome measures and disease biomarkers.NeuroRx 05/2006; 3(2):235-45.
Article: Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number.[show abstract] [hide abstract]
ABSTRACT: The survival motor neuron (SMN) transcript is encoded by two genes, SMNT and SMNC. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMNT gene. The SMNT gene can be distinguished from the SMNC gene by base-pair changes in exons 7 and 8. SMNT exon 7 is not detected in approximately 95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMNT now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMNT, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMNT and SMNC gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMNT copy number.The American Journal of Human Genetics 07/1997; 60(6):1411-22. · 10.60 Impact Factor