Myostatin as a therapeutic target in Amyotrophic Lateral Sclerosis

Walsh, Frank S.; Rutkowski, J Lynn

doi:10.1016/j.neuint.2012.07.016

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…However, SOD1 null mice, a model of amyotrophic lateral sclerosis, did not exhibit any improvements in survival (despite improvements in muscle mass) when exposed to myostatin inhibitors [56]. In another report, crossing of SMN null mice, a model of Spinal Muscular Atrophy, with myostatin null mice did not lead to increases in muscle mass or effects on survival [57], consistent with results using myostatin inhibitors from Sumner et al [58] but inconsistent with the positive effects reported by Rose et al [59].…”

Section: Progress In Validation Of Myostatin As a Target For Muscle Wmentioning

confidence: 96%

Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders

Smith¹,

Lin

2013

Current Opinion in Supportive &Amp; Palliative Care

133

131

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Purpose of reviewThis review summarizes recent progress in the development of myostatin inhibitors for the treatment of muscle wasting disorders. It also focuses on findings in myostatin biology that may have implications for the development of antimyostatin therapies.Recent findingsThere has been progress in evaluating antimyostatin therapies in animal models of muscle wasting disorders. Some programs have progressed into clinical development with initial results showing positive impact on muscle volume.In normal mice myostatin deficiency results in enlarged muscles with increased total force but decreased specific force (total force/total mass). An increase in myofibrillar protein synthesis without concomitant satellite cell proliferation and fusion leads to muscle hypertrophy with unchanged myonuclear number. A specific force reduction is not observed when atrophied muscle, the predominant therapeutic target of myostatin inhibitor therapy, is made myostatindeficient.Myostatin has been shown to be expressed by a number of tumor cell lines in mice and man.SummaryMyostatin inhibition remains a promising therapeutic strategy for a range of muscle wasting disorders.

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Section: Progress In Validation Of Myostatin As a Target For Muscle Wmentioning

confidence: 96%

Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders

Smith¹,

Lin

2013

Current Opinion in Supportive &Amp; Palliative Care

133

131

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“…34 Pharmacological inhibition of myostatin activity in rodents from either myostatin neutralizing antibodies, mutant myostatin propeptides or even decoy myostatin receptor-fusion proteins, results in increased muscle mass and improved muscle function. [37][38][39] As previously reported, a murine antibody termed RK35 was obtained through hybridoma technology. RK35 neutralizes mature myostatin signaling through activin receptor IIB (ActRIIB), and showed promising in vivo results, including slowing of muscle atrophy and grip strength loss in rodent models of ALS.…”

Section: Introductionmentioning

confidence: 99%

“…RK35 neutralizes mature myostatin signaling through activin receptor IIB (ActRIIB), and showed promising in vivo results, including slowing of muscle atrophy and grip strength loss in rodent models of ALS. 38,39 In this work, we initially demonstrate the successful humanization of the anti-myostatin antibody with a traditional CDR grafting approach onto clinically validated germline frameworks. 40 Following the traditional CDR grafting, we explored the further reduction of murine CDR content guided by co-crystal structures of the antibody:antigen complex.…”

Section: Introductionmentioning

confidence: 99%

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Apgar

Mader

Agostinelli

et al. 2016

mAbs

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Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies. To accomplish this, we solved the co-crystal structures of myostatin with the chimeric (Protein Databank (PDB) id 5F3B) and CDR-grafted antimyostatin antibody (PDB id 5F3H), allowing us to computationally predict the structurally important CDR residues as well as those making significant contacts with the antigen. Structure-based rational design enabled further germlining of the CDR-grafted antibody, reducing the murine content of the antibody without affecting antigen binding. The overall "humanness" was increased for both the light and heavy chain variable regions.

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Diagnostic and therapeutic potential of shark variable new antigen receptor (VNAR) single domain antibody

Cheong

Leow

Majeed

2020

International Journal of Biological Macromolecules

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Conventional monoclonal antibodies (mAbs) have been widely used in research and diagnostic applications due to their high affinity and specificity. However, multiple limitations, such as large size, complex structure and sensitivity to extreme ambient temperature potentially weaken the performance of mAbs in certain applications. To address this problem, the exploration of new antigen binders is extensively required in relation to improve the quality of current diagnostic platforms. In recent years, a new immunoglobulin-based protein, namely variable domain of new antigen receptor (VNAR) was discovered in sharks. Unlike conventional mAbs, several advantages of VNARs, include small size, better thermostability and peculiar paratope structure have attracted interest of researchers to further explore on it. This article aims to first present an overview of the shark VNARs and outline the characteristics as an outstanding new reagent for diagnostic and therapeutic applications.

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Myostatin as a therapeutic target in Amyotrophic Lateral Sclerosis

Cited by 4 publications

References 33 publications

Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders

Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Diagnostic and therapeutic potential of shark variable new antigen receptor (VNAR) single domain antibody

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