Unfounded Claims of Improved Functional Outcomes Attributed to Follistatin Gene Therapy in Inclusion Body Myositis

Greenberg, Steven A.

doi:10.1016/j.ymthe.2017.09.002

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…In a nonrandomized open-label study, 6 IBM patients were treated with follistatin gene therapy and showed improvement in the 6-min walk test (5-153 m) [114]. However, the treated group also received high-dose prednisone and a prescribed exercise program, which was not accounted for in the matched control group [115]. Therefore, further studies are needed to determine the efficacy of follistatin gene therapy in IBM.…”

Section: Targeting Degenerative Pathwaysmentioning

confidence: 99%

Inclusion Body Myositis: Update on Pathogenesis and Treatment

2018

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Inclusion body myositis is the most common acquired myopathy after the age of 50. It is characterized by progressive asymmetric weakness predominantly affecting the quadriceps and/or finger flexors. Loss of ambulation and dysphagia are major complications of the disease. Inclusion body myositis can be associated with cytosolic 5'-nucleotidase 1A antibodies. Muscle biopsy usually shows inflammatory cells surrounding and invading non-necrotic muscle fibers, rimmed vacuoles, congophilic inclusions, and protein aggregates. Disease pathogenesis remains poorly understood and consists of an interplay between inflammatory and degenerative pathways. Antigen-driven, clonally restricted, cytotoxic T cells represent a main feature of the inflammatory component, whereas abnormal protein homeostasis with protein misfolding, aggregation, and dysfunctional protein disposal is the hallmark of the degenerative component. Inclusion body myositis remains refractory to treatment. Better understanding of the disease pathogenesis led to the identification of novel therapeutic targets, addressing both the inflammatory and degenerative pathways.

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Section: Targeting Degenerative Pathwaysmentioning

confidence: 99%

Inclusion Body Myositis: Update on Pathogenesis and Treatment

2018

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“…This study observed an improvement in the distance traveled for a 6MWT, and all post-treatment biopsies showed increased number of muscle fibers [64]. However, significant concerns have been raised in regards to the design of this trial and the authors’ claim of efficacy [66]. Most importantly, the lack of a control group makes it difficult to determine how much of the improvement was a result of exercise and/or placebo effect.…”

Section: Gene Therapymentioning

confidence: 99%

New Developments in the Genetics of Inclusion Body Myositis

2018

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In a study of 252 IBM patients, the class II MHC allele HLA-DRB1*03:01 showed the most significant association with IBM, and that risk could be largely attributed to amino acids within the peptide-binding pocket. Candidate gene sequencing identified rare missense variants in proteins regulating protein homeostasis including VCP and SQSTM1. An unbiased approach employing exome sequencing of genes encoding rimmed vacuole proteins identified FYCO1 variants in IBM. Ongoing GWAS approaches may shed new light on genetic risk factors for IBM. Many variants have been reported at an increased frequency in IBM in small studies; however, only HLA association has shown genome-wide significance. Future studies are needed to validate variants in larger cohorts and to understand the molecular roles these risk factors play in IBM.

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“…Thus, some data were expressed qualitatively or were highly variable. These and other concerns over study design, blinding, and data normalization in the IBM study were raised in a letter to the editor ( 385 ) and have been addressed by the study director ( 386 ). Whether these concerns have influenced the status of future trials is unclear as none to date has been announced.…”

Section: Drug Development Statusmentioning

confidence: 99%

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs

Rodgers

Ward

2021

Endocrine Reviews

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Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders and of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling as these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of “inhibiting the inhibitors”, increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.

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Unfounded Claims of Improved Functional Outcomes Attributed to Follistatin Gene Therapy in Inclusion Body Myositis

Abstract: Morphological and behavioral impact of AAV2/ 5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system. PLoS One. 8, e81426.

Cited by 6 publications

References 14 publications

Inclusion Body Myositis: Update on Pathogenesis and Treatment

Inclusion Body Myositis: Update on Pathogenesis and Treatment

New Developments in the Genetics of Inclusion Body Myositis

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs

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