Clinical trial of L‐Carnitine and valproic acid in spinal muscular atrophy type I

Krosschell, Kristin J.; Kissel, John T.; Townsend, Elise L.; Simeone, Sarah D; Zhang, Ren Zhe; Reyna, Sandra P.; Crawford, Thomas O.; Schroth, Mary K.; Acsádi, Gyula; Kishnani, Priya S.; Kleist-Retzow, Jürgen-Christoph von; Hero, Barbara; D’Anjou, Guy; Smith, Edward C.; Elsheikh, Bakri; Simard, Louise R.; Prior, Thomas W.; Scott, Charles; LaSalle, Bernie; Sakonju, Ai; Wirth, Brunhilde; Swoboda, Kathryn J.

doi:10.1002/mus.25776

Cited by 24 publications

(15 citation statements)

References 40 publications

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“…Several different compounds have been investigated in randomized controlled trials in the last few decades, including approaches to increase muscle strength and function by (1) hyperacetylating agents such as valproic acid [28][29][30] or phenylbutyrate [31], (2) anabolic agents such as albuterol [32], thyreotropin-releasing hormone [33] or growthhormone [34] and 3neuroprotective agents such as gabapentin [35,36], riluzol [37] and olesoxime [38]. Despite negative results regarding primary endpoints, those investigations validated outcome measures and yielded key information about trial designs and the feasibility of patient recruitment.…”

Section: Therapeutic Approaches -Drug Treatmentmentioning

confidence: 99%

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

Schorling

Pechmann

Kirschner

2020

JND

163

126

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Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.

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Section: Therapeutic Approaches -Drug Treatmentmentioning

confidence: 99%

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

Schorling

Pechmann

Kirschner

2020

JND

163

126

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“…Despite the number of HDAC inhibitors tested and the encouraging results, only phenylbutyrate and VPA have entered clinical trials for human use. Valproic acid was tested in five Phase I/II clinical trials (NCT00374075, NCT00227266, NCT00481013, NCT00661453, and NCT01033331) [ 106 , 107 , 108 , 109 , 110 , 111 ] and showed outcomes variability. All the studies mentioned above were included in the meta-analysis performed by Elshafay et al [ 112 ] suggesting the VPA administration was safe, although some adverse effects were recorded, and it induced a major improvement of motor function.…”

Section: Genetic and Epigenetic Etiology Of Clinical Heterogeneitymentioning

confidence: 99%

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

Smeriglio

Langard

Querin

et al. 2020

JPM

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Spinal muscular atrophy (SMA) is currently classified into five different subtypes, from the most severe (type 0) to the mildest (type 4) depending on age at onset, best motor function achieved, and copy number of the SMN2 gene. The two recent approved treatments for SMA patients revolutionized their life quality and perspectives. However, upon treatment with Nusinersen, the most widely administered therapy up to date, a high degree of variability in therapeutic response was observed in adult SMA patients. These data, together with the lack of natural history information and the wide spectrum of disease phenotypes, suggest that further efforts are needed to develop precision medicine approaches for all SMA patients. Here, we compile the current methods for functional evaluation of adult SMA patients treated with Nusinersen. We also present an overview of the known molecular changes underpinning disease heterogeneity. We finally highlight the need for novel techniques, i.e., -omics approaches, to capture phenotypic differences and to understand the biological signature in order to revise the disease classification and device personalized treatments.

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“…Preclinical studies indicate that several of these compounds can be highly effective in rescuing SMA phenotypes 81 . Other studies have attempted to increase SMN protein levels either by inhibiting histone deacytelases, increasing STAT5 activity or inhibiting SMN ubiquitination [82][83][84][85][86] , but although these approaches seemed to hold promise in early preclinical experiments, clinical studies so far have been disappointing [87][88][89] .…”

Section: Advances In Sma Therapy Developmentmentioning

confidence: 99%

Advances in therapy for spinal muscular atrophy: promises and challenges

2018

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Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.

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Clinical trial of L‐Carnitine and valproic acid in spinal muscular atrophy type I

Cited by 24 publications

References 40 publications

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

Advances in therapy for spinal muscular atrophy: promises and challenges

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