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.

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

“…18,[53][54][55][56] We aimed to test a situation suitable for future patient care and chose oral application beginning on the first day of life (P0). Protein analysis of SMA animals at different disease stages demonstrates that there may be organ as well as time-dependent effects of HDACi treatment on SMN levels.…”

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

“…Similarly, necrosis in the tail, ear pinnae, feet, legs, anus, etc. is manifested in severe SMA mice when their survival is extended after treatment with therapeutic drugs (Narver et al 2008;Hua et al 2011;Passini et al 2011;Porensky et al 2012).…”

Anticancer Gene Transfer for Cancer Gene Therapy

“…Generally while the non-viral physical methods are cost effective and less invasive than a viral approach the efficiency of delivery is extremely low and so far there only few examples of clinical use of these methods. Most significantly exon skipping approaches using oligonucleotides have been used successfully in the clinic for Duchenne Muscular Dystrophy (van Deutekom et al, 2007;Kinali et al, 2009;Cirak et al, 2011) and antisense oligonucleotides for Spinal Muscular Atrophy are in clinical development at present (Passini et al, 2011). Another method of non-viral gene delivery utilizes advanced nano-chemistry and nanoparticles that are analyzed extensively in another chapter of this book and constitute an attractive approach when compared only with the more efficient viral systems.…”