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

Capo, Valentina; Penna, Sara; Merelli, Ivan; Barcella, Matteo; Scala, Serena; Basso-Ricci, Luca; Drăghici, Elena; Palagano, Eleonora; Zonari, Erika; Desantis, Giacomo; Uva, Paolo; Cusano, Roberto; Sergi, Lucia Sergi; Crisafulli, Laura; Moshous, Despina; Stepensky, Polina; Drabko, Katarzyna; Kaya, Zühre; Ünal, Ekrem; Gezdirici, Alper; Menna, Giuseppe; Serafini, Marta; Aiuti, Alessandro; Locatelli, Silvia L.; Carlo‐Stella, Carmelo; Schulz, Ansgar; Ficara, Francesca; Sobacchi, Cristina; Gentner, Bernhard; Villa, Anna

doi:10.3324/haematol.2019.238261

Cited by 27 publications

(21 citation statements)

References 49 publications

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“…Therefore, in some cases, MIOP patients may easily be mistaken initially as having acute leukemia or JMML 14,15 . The abundance of CD34+ in the peripheral blood provides the possibility to easily harvest stem cells, which may be used as a back‐up graft in high‐risk transplants (e.g., haploidentical HSCT) or as a stem cell source for novel gene therapies 16 …”

Section: Diagnosismentioning

confidence: 99%

“…14,15 The abundance of CD34+ in the peripheral blood provides the possibility to easily harvest stem cells, which may be used as a back-up graft in high-risk transplants (e.g., haploidentical HSCT) or as a stem cell source for novel gene therapies. 16 The ophthalmologic examination usually reveals optic nerve pallor due to optic atrophy, and in many cases, the patient is already blind at diagnosis. 17 Eventually, the diagnosis is made based on clinical presentation, many times with a significant family history, and a typical radiological presentation.…”

Section: Laboratory Findingsmentioning

confidence: 99%

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How we approach malignant infantile osteopetrosis

Even‐Or

Stepensky

2020

Pediatric Blood & Cancer

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Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder characterized by excessive bone overgrowth due to a defect in bone marrow resorption by osteoclasts. In most cases, hematopoietic stem cell transplantation (HSCT) may correct bone metabolism but the rapidly progressing nature of this condition necessitates early diagnosis and prompt treatment to minimize irreversible cranial nerve damage. The management of patients with MIOP presents many unique challenges. In this review, the clinical management of patients with MIOP is discussed, including diagnosis, preparation for HSCT and special transplant considerations, management of unique HSCT complications, and long-term follow-up.

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Section: Diagnosismentioning

confidence: 99%

Section: Laboratory Findingsmentioning

confidence: 99%

How we approach malignant infantile osteopetrosis

Even‐Or

Stepensky

2020

Pediatric Blood & Cancer

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“…HSPC expansion protocols assuring maintenance of stemness potential are currently being tested when limited donor cells are available, especially in case of cord blood donors (78,79). Notably, these protocols can be exploited to decrease the burden of CD34+ cell harvest in very young patients in gene therapy and editing settings (80). Conventional GT approach has shown promising results in murine models, highlighting at the same time the need for physiological level of RAG expression while maintaining low vector copy number.…”

Section: Discussionmentioning

confidence: 99%

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

2020

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Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between in vitro recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.

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“… 11 TCIRG1-mutated osteoclasts have a defective ruffled border and significantly reduced resorptive activity. 17 Mutations in the CLCN7 gene are associated with ARO and ADO type II. 18 CLCN7 is essential for bone remodeling, and mutations of the CLCN7 gene make the bone brittle.…”

Section: Discussionmentioning

confidence: 99%

<p>Subtrochanteric Femoral Fracture in a Patient with Osteopetrosis: Treated with Internal Fixation and Complicated by Intraoperative Femoral Neck Fracture</p>

Hua

Liu

Wang

2020

IJGM

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Objective Osteopetrosis (OP) is a rare, heritable skeletal disorder that is caused by osteoclast dysfunction, leading to failure of bone resorption and increased bone density. The fragility of such dense bone may result in an increased incidence of fractures. Furthermore, surgery in patients with OP is associated with increased technical difficulty and a higher risk of complications. Case Report We report a case of a 20-year-old woman with autosomal dominant OP who developed a subtrochanteric femoral fracture. The fracture was treated by open reduction and internal fixation using a dynamic hip screw. Although technical difficulties were experienced and an intraoperative femoral neck fracture occurred, the surgical outcome was satisfactory. Union of the fractures was visible on radiographs obtained 12 months postoperatively. At 2 years postoperatively, the patient was completely free of any complications resulting from her injury and treatment. Conclusion Open reduction and internal fixation may be an effective option for fractures in patients with OP. Orthopedic surgeons should be aware that the increased density and stiffness of osteopetrotic bone increases the risks of intraoperative technical difficulties, iatrogenic fractures, and postoperative complications.

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

Abstract: Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis.Abstract word count: 248

Cited by 27 publications

References 49 publications

How we approach malignant infantile osteopetrosis

How we approach malignant infantile osteopetrosis

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

<p>Subtrochanteric Femoral Fracture in a Patient with Osteopetrosis: Treated with Internal Fixation and Complicated by Intraoperative Femoral Neck Fracture</p>

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