title: Osteopetrosis rescue upon RANKL administration to Rankl(-/-) mice: a new therapy for human RANKL-dependent ARO.
abstract: In the last decades the molecular basis of monogenic diseases has been largely unraveled, although their treatment has often remained unsatisfactory. Autosomal recessive osteopetrosis (ARO) belongs to the small group of genetic diseases that are usually treated with hematopoietic stem cell transplantation (HSCT). However, this approach is not effective in the recently identified form carrying mutations in the receptor activator of NF-κB ligand (RANKL) gene. In this subset, therapy replacement approach based on RANKL delivery has a strong rationale. Here we demonstrate that the systematic administration of RANKL for 1 month to Rankl(-/-) mice, which closely resemble the human disease, significantly improves the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, we provide evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial.
authors: UOS/IRGB, Milan Unit, CNR, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Nadia
authors: N
authors: Lo Iacono
authors: Harry C
authors: HC
authors: Blair
authors: Pietro L
authors: PL
authors: Poliani
authors: Veronica
authors: V
authors: Marrella
authors: Francesca
authors: F
authors: Ficara
authors: Barbara
authors: B
authors: Cassani
authors: Fabio
authors: F
authors: Facchetti
authors: Elena
authors: E
authors: Fontana
authors: Matteo M
authors: MM
authors: Guerrini
authors: Elisabetta
authors: E
authors: Traggiai
authors: Francesca
authors: F
authors: Schena
authors: Marianna
authors: M
authors: Paulis
authors: Stefano
authors: S
authors: Mantero
authors: Antonio
authors: A
authors: Inforzato
authors: Serenella
authors: S
authors: Valaperta
authors: Alessandra
authors: A
authors: Pangrazio
authors: Laura
authors: L
authors: Crisafulli
authors: Virginia
authors: V
authors: Maina
authors: Paul
authors: P
authors: Kostenuik
authors: Paolo
authors: P
authors: Vezzoni
authors: Anna
authors: A
authors: Villa
authors: Cristina
authors: C
authors: Sobacchi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced; D001842:Bone and Bones / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010022:Osteopetrosis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D053245:RANK Ligand / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000172:deficiency / Q000235:genetics
chemical_list: D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B