Dual Masking of Specific Negative Splicing Regulatory Elements Resulted in Maximal Exon 7 Inclusion of SMN2 Gene

Pao, Peng Wen; Wee, Keng Boon; Yee, Woon Chee; DwiPramono, Zacharias Aloysius

doi:10.1038/mt.2013.276

Cited by 27 publications

(38 citation statements)

References 44 publications

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“…Although major progress has been made in patient care and support for breathing and nutrition, no treatment is available that halts or delays the degeneration of motor neurons and the connected muscular function. However, since the disease is caused by low amounts of SMN protein, several promising approaches are currently in pre-clinical and clinical trials aiming to increase SMN production 45,46 . Gene therapy is a promising approach to achieve this goal and is appealing due to the long-lasting effects of a single administration.…”

Section: Discussionmentioning

confidence: 99%

Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

et al. 2015

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Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus-9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, we evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. We found widespread transgene expression throughout the spinal cord in mice and nonhuman primates when using a 10 times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. We present a detailed analysis of transduction levels throughout the brain, brainstem, and spinal cord of nonhuman primates, providing new guidance for translation toward therapy for a wide range of neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

et al. 2015

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“…In addition, the potential for dual-masking ASOs that simultaneously sequester two targets could increase the repertoire of ASOs for SMA therapy. 80 Given the spectrum of the SMA phenotype, it will be useful to have multiple ASO targets so as to treat best treat patients who may not respond to specific ASOs.…”

Section: Discussionmentioning

confidence: 99%

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

et al. 2017

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Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.

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“…A recent report showed utility of an ASO targeting an antisense sequence of SMN2 [70]. In cell-based assays, a dual-masking ASO has shown a better efficacy than an ISS-N1 targeting ASO [71]. However, ISS-N1 still needs to be targeted to maintain the high efficacy of the dual-masking ASO [71].…”

Section: Clinical Development Of Spinraza™ For the Treatment Of Smamentioning

confidence: 99%

“…In cell-based assays, a dual-masking ASO has shown a better efficacy than an ISS-N1 targeting ASO [71]. However, ISS-N1 still needs to be targeted to maintain the high efficacy of the dual-masking ASO [71]. Currently, it is not known how a variety of targets may be affected by different ASO chemistries or treatment with a combination of ASOs, and thus all ASO targets remain of interest for future research.…”

Section: Clinical Development Of Spinraza™ For the Treatment Of Smamentioning

confidence: 99%

ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

Ottesen

2017

Translational Neuroscience

140

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Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

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Dual Masking of Specific Negative Splicing Regulatory Elements Resulted in Maximal Exon 7 Inclusion of SMN2 Gene

Cited by 27 publications

References 44 publications

Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

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