Limits...
Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders.

Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K, Abdelmagid SM - Biomed Res Int (2014)

Bottom Line: Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP.Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed.There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

View Article: PubMed Central - PubMed

Affiliation: Nova Southeastern University Health Sciences Division, Fort-Lauderdale-Davie, FL 33314, USA.

ABSTRACT
A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

Show MeSH

Related in: MedlinePlus

Summary of the pathogenesis of FOP and potential therapeutic interventions.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4230237&req=5

fig6: Summary of the pathogenesis of FOP and potential therapeutic interventions.

Mentions: Importantly, while inhibitors of ALK2 including LDN-193189 and dorsomorphin are effective in reducing ALK2 activity, they also block the activity of another BMP receptor, BMPR1 (ALK3) activity [37]. Thus, any viable therapeutic intervention would be one that blocks the hyperactivity of ALK2 without impacting the other kinases in the pathway [33]. Kaplan et al. were able to identify siRNAs which target the ALK2 causing pathology while the normal ALK2 remained unaffected [37, 38]. Thus, siRNAs from FOP patients have been utilized to retain normal activity of BMP [37, 38]. Kaplan et al. [38] demonstrated selective suppression of mutated ACVR1 by utilizing ASP-RNAi (allele-specific RNA interference) techniques. This study showed a promising glimpse of the possibility of shutting down ACVR1 activity. Yet, further work is needed to develop an effective regimen of ACVR1 suppression in humans. Figure 6 summarizes the pathogenesis and possible therapeutic strategies that may target FOP.


Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders.

Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K, Abdelmagid SM - Biomed Res Int (2014)

Summary of the pathogenesis of FOP and potential therapeutic interventions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230237&req=5

fig6: Summary of the pathogenesis of FOP and potential therapeutic interventions.
Mentions: Importantly, while inhibitors of ALK2 including LDN-193189 and dorsomorphin are effective in reducing ALK2 activity, they also block the activity of another BMP receptor, BMPR1 (ALK3) activity [37]. Thus, any viable therapeutic intervention would be one that blocks the hyperactivity of ALK2 without impacting the other kinases in the pathway [33]. Kaplan et al. were able to identify siRNAs which target the ALK2 causing pathology while the normal ALK2 remained unaffected [37, 38]. Thus, siRNAs from FOP patients have been utilized to retain normal activity of BMP [37, 38]. Kaplan et al. [38] demonstrated selective suppression of mutated ACVR1 by utilizing ASP-RNAi (allele-specific RNA interference) techniques. This study showed a promising glimpse of the possibility of shutting down ACVR1 activity. Yet, further work is needed to develop an effective regimen of ACVR1 suppression in humans. Figure 6 summarizes the pathogenesis and possible therapeutic strategies that may target FOP.

Bottom Line: Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP.Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed.There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

View Article: PubMed Central - PubMed

Affiliation: Nova Southeastern University Health Sciences Division, Fort-Lauderdale-Davie, FL 33314, USA.

ABSTRACT
A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

Show MeSH
Related in: MedlinePlus