A new study from the Braddock Laboratory at Yale School of Medicine sheds light on the pathogenesis of two debilitating spinal disorders prevalent in the aging population—ossification of the posterior longitudinal ligament (OPLL) and diffuse idiopathic skeletal hyperostosis (DISH).
These diseases lead to stiffness and severe chronic pain, increased risk of spinal fractures, and, in severe cases, hemiplegia. Current therapies are limited to analgesics for pain and spinal surgery, which can be complicated by rapid recalcification of the spine.
The study, published in the Journal of Bone and Mineral Research, explores the underlying cause of these conditions and presents a potential groundbreaking therapy. The study involved a dual approach: a prospective analysis of OPLL patients presenting for surgical correction at the University of Tokyo and the preclinical efficacy of innovative therapeutics in OPLL murine models at Yale.
The study spanned three continents and involved numerous investigators. The authors identified a pathogenic mechanism for the disease and were able to show significant improvement in the phenotype by using novel therapeutics. The research was led jointly by Braddock Lab members Shivani Srivastava, PhD, and Hajime Kato, MD, PhD, and involved investigators from University of Tokyo Hospital System and University of Hamburg Medical Center.
“Our study represents a significant leap forward in understanding the pathology of OPLL and DISH,” says Demetrios Braddock, MD, PhD, professor of pathology and senior author of the study. “The positive outcomes observed with ENPP1 enzyme therapy in murine models are encouraging, and we hope this paves the way for human trials. We are optimistic that our continued efforts will lead to a viable treatment option for patients suffering from these debilitating conditions.”
In the study, OPLL patients demonstrated plasma biomarkers that are characteristic of patients with a form of ENPP1 deficiency— a disease caused by mutations in the ENPP1 gene—called autosomal recessive hypophosphatemic rickets type 2, suggesting that defects in the ENPP1 pathway may be contributing to the disease pathogenesis.
The second phase of the study, involving the preclinical efficacy of innovative therapeutics in OPLL murine models, tested this hypothesis by targeting the ENPP1 pathway with a bone-targeted isoform of ENPP1 in preclinical OPLL murine models. The results were promising as the therapy corrected plasma biochemical abnormalities, showing that targeting the ENPP1 pathway in preclinical murine models led to significant reduction in spinal hyperostosis and normalization of spinal fracture risk. In addition, tendon enthesopathies, which often accompany these conditions, showed marked recovery
The identification of plasma biomarkers in OPLL patients not only provides insights into the disease mechanism but also establishes a foundation for targeted therapies. The research team now aims to translate these findings from animal models to human clinical trials, which could revolutionize treatment strategies for OPLL and DISH, Braddock says.
The Braddock Lab is focused on the study of severe, poorly addressed human disease with an emphasis on the elucidation of disease pathogenesis to unveil therapeutic targets. Braddock has a particular interest in rare diseases of children and the design and engineering of novel biologics to modulate disease outcome.
Additional Yale authors include Keith Weise, Paul Stabach, Sam G. Lopez, Ethan R. Lester, Hana Kim, Tayyaba Ishaq, Thomas O. Carpenter, and Steven Tommasini. Other authors are Simon von Kroge, Ralf Oheim, and Thorsten Schinke, University Medical Center, Hamburg; Nobuaki Ito, Soichiro Kimura, Toru Doi, and Yasushi Oshima, University of Tokyo; Kris Dammen-Brower, Junya Miyahara, and Kevin J. Yarema, Johns Hopkins University; and Yves Sabbagh and Kevin O’Brien, Inozyme Pharma, Boston.