Posted December 10, 2021

Elizabeth McNally, M.D, Ph.D, Northwestern University
Alexis Demonbreun, Ph.D., Northwestern University

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by changes in the dystrophin protein and characterized by muscle degeneration and weakness in the entire body. DMD is progressive and eventually compromises lung and heart functions. There is no cure for DMD, and patients typically do not survive past their 30s. Steroids are the primary treatment to slow DMD progression and improve muscle strength; however, there are significant side effects with the current standard dosing, including: weight gain, behavior issues, osteoporosis, and hormone changes. Newer treatments that work by skipping over the genetic mutations in the dystrophin gene, i.e., exon skipping, can moderately improve the condition; however, they only work for a small number of patients with specific genetic mutations. There is a significant need for new DMD therapeutics that are applicable to all individuals with DMD and that can be combined with lower dose steroids to improve patient outcomes but also reduce side effects. Initial results from Demonbreun, McNally, and their team using a DMD mouse model showed anti-LTBP4 antibodies combined with a lower dose steroid regimen lead to improvements in muscle function and protection from injury.

With a Fiscal Year 2017 (FY17) Investigator-Initiated Research Award from the Duchenne Muscular Dystrophy Research Program (DMDRP), the team at Northwestern evaluated a novel DMD antibody treatment that combines targeting of latent transforming growth factor β (TGF-β) binding protein 4 (LTBP4) with a lower dose steroid regimen. One of LTBP4's functions is modulating availability of TGF-β, which is implicated in downstream signaling cascades that contribute to muscle fibrosis and weakness. Previous work by Dr. McNally's group identified LTBP4 as a genetic modifier of muscular dystrophy in mice.¹ In humans, certain single nucleotide polymorphisms in LTBP4 are also known to affect ambulation outcomes of individuals with DMD by either binding tightly or more loosely to TGF-β.2 Using a FY12 Therapeutic Idea Award from the DMDRP, Dr. McNally explored generating antibodies to target LTBP4 in an effort to stabilize the protein and prevent release of TGF-β. Initial results from the experiments in this award were highly promising.

With the FY17 award, the team evaluated new antibodies in a preclinical mouse model of DMD (mdx mice), relying on high-affinity, human monoclonal anti-LTBP4 antibodies to bind LTBP4. In a recent publication in Science Translational Medicine, results demonstrated that mdx mice treated with the monoclonal anti-LTBP4 antibodies showed reduced muscle fibrosis, increased protection from muscle injury, improved muscle size and performance, and improved respiratory function. The team also tested the novel monoclonal anti-LTBP4 antibody in combination with a lower dose steroid regimen in mdx mice and found this combination showed even further improvements in muscle function and protection from injury. This result is significant because lower doses of steroids in combination with anti-LTBP4 antibody treatment could mean fewer side effects for individuals with DMD. Further preclinical mouse studies are ongoing, including serum profiling of muscle injury biomarkers and RNA sequencing of muscle samples to evaluate TGF-β signaling pathways, with the goal of developing clinical biomarkers that could be used in any future human studies of this novel therapeutic.

With support from two DMDRP awards, Dr. McNally and Dr. Demonbreun have been able to extend their work by developing and evaluating a combination therapy of anti-LTBP4 antibodies with a lower dose steroid regimen. This powerful combination treatment could greatly improve the quality of life and longevity of individuals living with DMD.

Publication:

Demonbreun AR, Fallon KS, Oosterbaan CC, et al. 2021. Anti-latent TGFβ binding protein 4 antibody improves muscle function and reduces muscle fibrosis in muscular dystrophy. Sci Transl Med. 13(610):eabf0376. doi: 10.1126/scitranslmed.abf0376. Epub 2021 Sep 8. PMID: 34516828.

References:

¹ Heydemann A, Ceco E, Lim JE, et al. 2009. Latent TGF-β-binding protein 4 modifies muscular dystrophy in mice. J Clin Invest. 119:3703-3712.

² Flanigan KM, Ceco E, Lamar KM, et al. 2013. LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol. 2013 Apr;73(4):481-488. doi: 10.1002/ana.23819. Epub 2013 Feb 20. PMID: 23440719; PMCID: PMC4106425.

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