Osteopetroses, emphasizing potential approaches to treatment

Abstract

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.

Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease

“…Symptoms and signs of Albers-Schönberg disease generally appear in childhood or adolescence, and there is wide phenotypic variability within and across families. The phenotype in persons with Albers-Schönberg disease can cause debilitating problems and worsen over time, and no beneficial pharmacological therapy is currently available [3–5]. …”

Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis

“…Infusion of autologous gene corrected HSPCs may represent an attractive therapy to avoid the risk of severe graft-versus-host-disease reactions and limit complications caused by intensive myeloablative conditioning. Gene therapy would also allow treatment of patients without compatible donors or whose severe clinical conditions and/or age preclude conventional therapy 7,40 . In addition, mild forms of TCIRG1 osteopetrosis have been recently identified in adult patients rising concerns about the risk of lifethreating complications during conventional therapy 41 .…”

“…Children with osteopetrosis suffer from high rates of graft failure and transplantrelated mortality, mostly due to severe graft-versus-host disease, liver toxicity (venoocclusive disease), infections or lung toxicity (idiopathic pneumonia syndrome and acute respiratory distress syndrome) 7,8 . In particular, transplants from HLA-matched related or unrelated donors have an 80-88% five-year disease-free survival, whereas the success rate is lower for haploidentical transplants (66%) 2 .…”

Generalized osteopetrosis: indications, efficacy and peculiarities of hematopoietic stem cell transplantation (own experience)

“…В зависимости от возраста манифестации и степени выраженности клинических симптомов различают 3 основные формы ГО: аутосомно-доминантную (OMIM:166600; 607634); летальную аутосомно-рецессивную (OMIM:259700); умереннотяжелую аутосомно-рецессивную (OMIM:259710) [1][2][3].…”

“…В последнем случае заболевание протекает наиболее тяжело, что обусловлено наличием гомозиготного состояния по мутантному аллелю. Всем пациентам с ГО показано назначение симптоматической терапии, направленной на коррекцию выявляемых расстройств [2,3].…”