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Review
. 2019 Dec 30;14(1):300.
doi: 10.1186/s13023-019-1222-2.

The evolving therapeutic landscape of genetic skeletal disorders

Ataf Hussain Sabir  1 , Trevor Cole  2
Affiliations
Review

The evolving therapeutic landscape of genetic skeletal disorders

Ataf Hussain Sabir et al. Orphanet J Rare Dis. .

Abstract

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.

Keywords: Bone; Dysplasia; Genetic; Hereditary; Personalised; Rare; Skeletal; Targeted; Therapy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow diagram illustrating search strategy
Fig. 2
Fig. 2
Rugger Jersey Spine in Osteopetrosis. Images taken from radiopedia.org under creative commons license 3.0 [32]
Fig. 3
Fig. 3
HPP mechanism of disease. Image used under the creative commons attribution license 3.0 from Bowden et al. [69]
See this image and copyright information in PMC

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