BACKGROUND Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. METHODS A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. RESULTS Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. DISCUSSION It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.

中文翻译：

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遗传性骨骼疾病不断发展的治疗前景。

背景 罕见骨病占所有出生缺陷的 5%，但很少有骨病能够进行个性化治疗。然而，基因诊断、分子技术和治疗技术的发展正在带来无与伦比的治疗进步。这篇综述探讨了遗传性骨骼疾病（GSD）不断发展的治疗前景；关键条件和关键差异。方法 2018 年 12 月，我们使用系统检索策略分别在 Pubmed 和 ClinicalTrials.gov 上对相关文章和试验进行了回顾性文献综述。生成了 140 多篇文章和 80 多项试验供审查。结果 除了超过 25 个 GSD 中的几种新型疾病缓解疗法之外，还讨论了超过 20 种个性化疗法。讨论的治疗方法处于从临床前研究到临床试验和批准药物的不同阶段，包括：用于治疗 X 连锁低磷血症的 Burosumab、用于治疗遗传性多发性外生骨疣的 Palovarotene、用于治疗干骺端软骨发育不良（Schmid 型）的卡马西平、用于治疗骨质疏松症假神经胶质瘤综合征的碳酸锂和抗硬化素治疗以及用于骨质疏松症的新疗法。我们还讨论了软骨发育不全、成骨不全 (OI)、磷酸酶减退 (HPP)、进行性骨化性纤维发育不良以及 OI 和 HPP 临床前研究中的 RNA 沉默疗法的治疗进展。讨论 尽管罕见疾病药物开发面临挑战，但对于 GSD 疗法来说，这是一个激动人心的时刻。在讨论新兴疗法时，我们探索从药物再利用到子宫内干细胞移植的药物开发新方法。我们强调对骨病理生理学、遗传途径和开发 GSD 基因疗法的挑战的进一步了解。