SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Swoboda, Kathryn J.; Scott, Charles; Crawford, Thomas O.; Simard, Louise R.; Reyna, Sandra P.; Krosschell, Kristin J.; Acsádi, Gyula; Elsheik, Bakri; Schroth, Mary K.; D’Anjou, Guy; LaSalle, Bernie; Prior, Thomas W.; Sorenson, Susan; Maczulski, Jo Anne; Bromberg, Mark B.; Chan, Gary M.; Kissel, John T.

doi:10.1371/journal.pone.0012140

Cited by 158 publications

(129 citation statements)

References 35 publications

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“…27,[29][30][31] However, the clinical benefit of the substances tested to date remains uncertain. 21,[32][33][34][35] A complete rescue of the phenotype by HDACi application is unlikely to be achieved for patients most severely affected and only possessing a low number of SMN2 copies, and thereby restricted potential for increase in FL protein expression. Nonetheless, improvement of quality of life is still an objective worth investigating for these patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by a-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of -primary or secondary -non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…The use of HDAC inhibitors has been well advanced in the field of cancer, with many tested in clinical trials, and three approved for cancer therapy (reviewed in Mottamal et al 2015). Phase II clinical trials for the use of HDAC inhibitors for the treatment of the motor neuron disease, spinal muscular atrophy (SMA), yielded initial encouraging results, although these were not confirmed or extended by later studies (Mercuri et al 2004(Mercuri et al , 2007Swoboda et al 2010;Kissel et al 2011Kissel et al , 2014. More research on the specific targets of acetylation, the specific enzymes involved, and the development of more directed compounds are likely required.…”

Section: Establishing a Modelmentioning

confidence: 99%

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

2015

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With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research.

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“…To date, the 26 clinical trials that have investigated the effect of 12 potential treatments in patients with SMA have failed to show benefit owing to a number of factors, yet have enabled expertise in trial design to be developed [106,107]. Experience has suggested that younger patients might be more responsive to treatment [107,108]. Older patients may be refractive to treatment because they have been living with their disease for longer periods of time or because critical tissues have been irreversibly damaged.…”

Section: Challenges Is Smn1-related Sma Therapeuticsmentioning

confidence: 99%

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

2015

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Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

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SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Cited by 158 publications

References 35 publications

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

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

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

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