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      SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

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          Abstract

          Background

          Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.

          Methods

          This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.

          Results

          Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.

          Conclusions

          This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA.

          Trial Regsitration

          Clinicaltrials.gov NCT00227266

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          Most cited references38

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          Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy.

          Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
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            Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.

            Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder causing infant death in half of all patients. Homozygous absence of the survival motor neuron gene (SMN1) is the primary cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies. One SMN2 copy produces only about 10% of full-length protein identical to SMN1, whereas the majority of SMN2 transcripts is aberrantly spliced due to a silent mutation within an exonic splicing enhancer in exon 7. However, correct splicing can be restored by over-expression of the SR-like splicing factor Htra2-beta 1. We show that in fibroblast cultures derived from SMA patients treated with therapeutic doses (0.5-500 microM) of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. Importantly, this up-regulation of SMN could be most likely attributed to increased levels of Htra2-beta 1 which facilitates the correct splicing of SMN2 RNA as well as to an SMN gene transcription activation. Especially at low VPA concentrations, the restored SMN level depended on the number of SMN2 copies. Moreover, VPA was able to increase SMN protein levels through transcription activation in organotypic hippocampal brain slices from rats. Finally, VPA also increased the expression of further SR proteins, which may have important implications for other disorders affected by alternative splicing. Since VPA is a drug highly successfully used in long-term epilepsy therapy, our findings open the exciting perspective for a first causal therapy of an inherited disease by elevating the SMN2 transcription level and restoring its correct splicing.
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              Valproic acid increases SMN levels in spinal muscular atrophy patient cells.

              Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7-containing SMN transcript and SMN protein in type I SMA patient-derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                6 July 2011
                : 6
                : 7
                : e21296
                Affiliations
                [1 ]Departments of Neurology and Pediatrics, The Ohio State University, Columbus, Ohio, United States of America
                [2 ]CBS Squared, Inc, Fort Washington, Pennsylvania, United States of America
                [3 ]Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
                [4 ]Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
                [5 ]Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [6 ]Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
                [7 ]Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
                [8 ]Departments of Neurology and Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, United States of America
                [9 ]Department of Pediatrics, University of Wisconsin School of Medicine, Madison, Wisconsin, United States of America
                [10 ]Division of Pediatric Neurology, Hôpital Sainte-Justine Montréal, Montréal, Québec, Canada
                [11 ]Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
                [12 ]Department of Molecular Pathology, Ohio State University, Columbus, Ohio, United States of America
                [13 ]Primary Children's Medical Center, Salt Lake City, Utah, United States of America
                [14 ]Pediatric Occupational Therapy Services, Chicago, Illinois, United States of America
                [15 ]Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America
                Brigham and Women's Hospital, Harvard Medical School, United States of America
                Author notes

                Conceived and designed the experiments: JTK SPR TOC LS KJK GA BE MKS GD BL JAM KJS. Performed the experiments: JTK SPR TOC LS KJK GA BE MKS GD BL JAM KJS. Analyzed the data: BL CBS GMC. Contributed reagents/materials/analysis tools: TWP LS BL MBB SR. Wrote the paper: JTK SR TOC KS.

                Article
                PONE-D-10-03798
                10.1371/journal.pone.0021296
                3130730
                21754985
                903e5200-ce27-43f7-8309-ecb6533ff82b
                Kissel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 20 October 2010
                : 27 May 2011
                Page count
                Pages: 11
                Categories
                Research Article
                Medicine
                Clinical Genetics
                Neurology
                Developmental and Pediatric Neurology
                Neurodegenerative Diseases
                Neuromuscular Diseases
                Pediatrics
                Child Development

                Uncategorized
                Uncategorized

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