Haematopoietic Stem Cell Transplantation in Autosomal Recessive Osteopetrosis

Teti, Anna; Schulz, Ansgar

doi:10.1201/b14590-19

Cited by 3 publications

(3 citation statements)

References 40 publications

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“…This phenotype is due to a lysosomal 12 storage disease and is most reproducible in OSTM1-patients, while the situation is more heterogeneous in CLCN7-patients (18).…”

Section: Recessive Osteopetrosesmentioning

confidence: 99%

“…Although there have been many improvements in HSCT over the years, it remains a dangerous procedure with many toxicities (18). Therefore, it is reserved for patients with severe disease.…”

Section: Current Therapiesmentioning

confidence: 99%

“…However, the serious neurodegeneration observed in brain and retina, especially in OSTM1 deficient patients, cannot be cured by this procedure, therefore cognitive function and vision remain severely compromised (18). However, while the OSTM1 form Hypercalcemia is also observed, especially after HLA-identical transplant, which can require treatment with anti-resorptive drugs, including bisphosphonates or denosumab (18).…”

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confidence: 99%

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Osteopetroses, emphasizing potential approaches to treatment

Teti

Econs

2017

Bone

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Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure.Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.

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“…This phenotype is due to a lysosomal 12 storage disease and is most reproducible in OSTM1-patients, while the situation is more heterogeneous in CLCN7-patients (18).…”

Section: Recessive Osteopetrosesmentioning

confidence: 99%

“…Although there have been many improvements in HSCT over the years, it remains a dangerous procedure with many toxicities (18). Therefore, it is reserved for patients with severe disease.…”

Section: Current Therapiesmentioning

confidence: 99%

mentioning

confidence: 99%

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