Emerging targeted drug therapies in skeletal dysplasias

Abstract

Quantum advances have occurred in the field of human genetics in the six decades since Watson and Crick expressed their “wish to suggest a structure for the salt of deoxyribose nucleic acid.” These culminated with the human genome project, which has opened up myriad possibilities, including that of individualized genetic medicine, the ability to deliver medical advice, management, and therapy tailored to an individual's genetic blueprint. Advances in genetic diagnostic capabilities have been rapid, to the point where the genome can be sequenced for several thousand dollars. Crucially, it has facilitated the identification of targets for “precision” treatments to combat genetic diseases at their source. This manuscript will review the innovative, pathogenesis‐based therapies that are revolutionizing management of skeletal dysplasias, giving patients and families new options and outcomes. © 2016 Wiley Periodicals, Inc.

Skeletal Dysplasias: Growing Therapy for Growing Bones

“…There are over a dozen types of OI with a prevalence of 1–2 per 20,000 children (Yap and Savarirayan, 2016). Pathogenic mutations in OI have been uncovered in the following genes: COL1A1, COL1A2, SERPINF1, CRTAP, LEPRE1, PPIB, SERPINHI , or FKBP10 .…”

“…Pathogenic mutations in OI have been uncovered in the following genes: COL1A1, COL1A2, SERPINF1, CRTAP, LEPRE1, PPIB, SERPINHI , or FKBP10 . The majority of cases are due to an autosomal dominant mutation in COL1A1 and COL1A2 resulting in types I–IV, classified based on severity (Yap and Savarirayan, 2016). These mutations affect formation of type I collagen, which is the most prominent connective tissue in bone and skin.…”

“…Hypophosphatasia (HPP) is a rare metabolic disorder resulting from a loss-of-function mutation in the ALPL gene with corresponding deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) (Millán and Plotkin, 2012; Whyte et al, 2015; Yap and Savarirayan, 2016). There are 6 recognized clinical forms of HPP with varied severity, all correlated to insufficient mineralization of bone and teeth as well as osteomalacia in adults (Yap and Savarirayan, 2016).…”

“…There are 6 recognized clinical forms of HPP with varied severity, all correlated to insufficient mineralization of bone and teeth as well as osteomalacia in adults (Yap and Savarirayan, 2016). Although, mild forms of HPP are found in adolescents and adults, HPP that manifests in the fetus is almost always associated with infantile and perinatal lethality (Millán and Plotkin, 2012; Yap and Savarirayan, 2016) due to abnormal skeletal development and respiratory complications resulting from a small chest with pulmonary hypoplasia (Nishioka et al, 2006). …”

“…Asfotase alfa is a human recombinant TSNALP currently used to safely treat HPP by reestablishing TSNALP levels for proper degradation of inorganic pyrophosphate and consequential regulated bone mineralization (Nishioka et al, 2006; Whyte et al, 2016; Yap and Savarirayan, 2016). One study of this subcutaneous form of enzyme replacement therapy has demonstrated increased strength and agility as a result of improved bone mineralization (Whyte et al, 2016).…”