Demonbreun et al identify a novel antibody mediated therapeutic strategy for Duchenne muscular dystrophy based on previous genetic modifier studies.

by Jim Dowling

Publication

Anti-latent TGFβ binding protein 4 antibody improves muscle function and reduces muscle fibrosis in muscular dystrophy.
Demonbreun AR, Fallon KS, Oosterbaan CC, Vaught LA, Reiser NL, Bogdanovic E, Velez MP, Salamone IM, Page PGT, Hadhazy M, Quattrocelli M, Barefield DY, Wood LD, Gonzalez JP, Morris C, McNally EM.
Sci Transl Med. 2021 Sep 8;13(610):eabf0376. doi: 10.1126/scitranslmed.abf0376. Epub 2021 Sep 8.
https://pubmed.ncbi.nlm.nih.gov/34516828/

Summary

There continues to be a great unmet need to identify and develop therapies for Duchenne muscular dystrophy. One exciting avenue for discovering new treatment strategies is to take advantage of genetic modifiers that influence the phenotypic expression of the disease. Previously, the team of Dr Elizabeth McNally, the senior author of the current study, identified in an unbiased screen Ltbp4 (latent TGF beta binding protein 4) as a modifier of murine muscular dystrophy. The relevance of this finding for human muscular dystrophy was later confirmed by the discovery of LTBP4 as a modifier of ambulatory status in DMD boys. Additional study using mouse models revealed that the protective Ltbp4 allele was resistant to proteolysis, enabling persistence of stable LTBP4 that could sequester TGFb and thereby reduce the fibrosis that results from excessive TGFb signalling in muscular dystrophies.

The highlighted manuscript, published in September in Science Translational Medicine, capitalizes on these observations. In this elegant study, the authors develop and test a monoclonal antibody to LTBP4. This antibody binds to the hinge region of the protein, thereby blocking it from being proteolytically cleaved, and thus mimicking the result of the protective Ltbp4 modifier allele. They first determined that antibody infusion in the mouse results in long lasting expression that is targeted to muscle and that reduces the molecular consequences of excessive TGFb signalling. Next, the authors examined the efficacy of both short and long term treatments on disease relevant outcomes in the mdx mouse (a DMD mouse model). They found significant reduction in fibrosis, protection from sarcolemmal damage, and enhanced recovery from muscle injury. In terms of functional measures, treatment with anti-LTBP4 enhanced muscle force generation and improved respiratory function. Importantly, no adverse events were noted, and no evidence of immune response was detected. In addition, the antibody worked synergistically with prednisone treatment, enhancing muscle function and limiting myofiber injury to a greater extent than either therapy alone. In total, the authors convincingly demonstrate that an antibody directed at LTBP4 can meaningfully ameliorate key aspects of the disease phenotype in the mdx mouse model of DMD.

Moving forward, anti-LTBP4 therapy is an attractive approach for the treatment of muscular dystrophy. It is DMD mutation agnostic, so would be potentially applicable to any DMD patient. Furthermore, its mechanism of action (reducing fibrosis mediated by excessive TGFb signalling) is potentially applicable to other forms of muscular dystrophy as well. Additional pre-clinical work, particularly related to toxicology, will be necessary before considering advance of this promising strategy to study in patients.


About the Author

Dr Alexis Demonbreun

I obtained my Ph.D. in Developmental Biology from the University of Chicago where I developed my interest in muscle regeneration and repair.  I am currently an Assistant Professor in the Center for Genetic Medicine, Department of Pharmacology at Northwestern University’s Feinberg School of Medicine.  My work focuses on understanding the genetic mechanisms of myopathies and using these genetic signals to drive therapy development.  I am currently pursuing the development of two biologics to treat muscle injury and disease.

This article is presented by the

Publication Highlights Committee.

Published on 1 November 2021.

Related

23 Oct 2024 ABCD3: the first oculopharyngodistal myopathy-related gene in European ancestry

16 Jan 2024 Anti-cN1A antibodies: epiphenomenon or pathogenic?

15 Nov 2023 Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, p

WMS Twitter Feed
WMS Facebook Feed