The prevalence of ENPP1 deficiency and the preclinical efficacy of ENPP1 biologic therapy in OPLL.

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Abstract
Ossification of the Posterior Longitudinal Ligament (OPLL) and Diffuse Idiopathic Skeletal Hyperostosis (DISH) are disorders in which patients suffer from pain and stiffness due to progressive spinal fractures and enthesospathy. Myelopathy and impaired mobility worsen with age and may progress to hemiplegia; the mechanisms driving disease progression are unknown, and effective treatments are lacking. To investigate OPLL disease pathogenesis we prospectively quantiated plasma PPi in consecutive OPLL and cervical osteoarthritic (OA) patients who presented for surgical correction, and further sequenced the OPLL patients for genes associated with phosphate wasting and spinal enthesopathy, and to evaluate novel OPLL therapeutics we explored the efficacy of soluble and bone targeted ENPP1 biologics on the plasma biomarkers and the skeletal phenotype of OPLL mice. We found that a significant proportion of OPLL patients harbored monoallelic pathogenic ENPP1 loss of function variants and that those OPLL patients requiring surgical intervention had significantly reduced plasma PPi levels in comparison to cervical OA patients with comparably severe disease. In murine OPLL, bone targeted ENPP1-Fc corrected plasma biomarkers and spinal hyperostosis, significantly improved or normalized spinal and long bone fragility, and ameliorated Achilles tendon enthesopathy. Our findings support the notion that OPLL patients are ENPP1 deficient, and that treatment with ENPP1 biologics may ameliorate the spinal hyperostosis, fracture risk, and enthesopathies present in OPLL.

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