One Disease, Many Genes: Implications for the Treatment of Osteopetroses

Abstract

Osteopetrosis is a condition characterized by increased bone mass due to defects in osteoclast function or formation. In the last decades, the molecular dissection of osteopetrosis has unveiled a plethora of molecular players responsible for different forms of the disease, some of which present also primary neurodegeneration that severely limits the therapy. Hematopoietic stem cell transplantation can cure the majority of them when performed in the first months of life, highlighting the relevance of an early molecular diagnosis. However, clinical management of these patients is constrained by the severity of the disease and lack of a bone marrow niche that may delay immune reconstitution. Based on osteopetrosis genetic heterogeneity and disease severity, personalized therapies are required for patients that are not candidate to bone marrow transplantation. This review briefly describes the genetics of osteopetrosis, its clinical heterogeneity, current therapy and innovative approaches undergoing preclinical evaluation.

Csf1 Signaling Regulates Maintenance of Resident Macrophages and Bone Formation in the Mouse Cochlea

“…In such cases, there are also reports that cochlear implants have been useful in patients with osteopetrosis who have deafness (17). Although osteopetrosis is genetically diverse, mutations in CSF1 have been reported as autosomal recessive in humans (18). In the present study, Csf1 op / op mice showed no nerve compression; therefore, hearing loss is thought to be largely due to conductive components such as spongy dysplasia of bone tissue in the ossicles and otic capsule.…”

RANKL biology: bone metabolism, the immune system, and beyond

“…Because the bone marrow space is preserved by osteoclastic bone resorption within the bone, RANKL functions as a maintainer of the bone marrow and its indwelling immune cells. In most types of osteopetrosis, the patients exhibit mild to severe hematological defects, which can lead to anemia, hemorrhage, and severe or recurrent infectious diseases [55,56].…”

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

“…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 . However, contrary to other inherited diseases treated with gene therapy 42 , the development of novel strategies is required in osteopetrosis to overcome clinical limitations that may hamper gene therapy applicability 43 . For this reason, we developed a tailored approach for the treatment of TCIRG1-mutated osteopetrosis exploiting autologous HSPC gene correction and expansion.…”