sirolimus and Genetic-Diseases--Inborn

Mutations affecting the genes that encode upstream components in the mammalian (or mechanistic) target of rapamycin signalling pathway are associated with a group of rare inherited and developmental disorders that show overlapping clinical features. These include predisposition to a variety of benign or malignant tumours, localized overgrowth, developmental abnormalities of the brain, neurodevelopmental disorders and epilepsy. Many of these features have been linked to hyperactivation of signalling via mammalian target of rapamycin complex 1, suggesting that inhibitors of this complex such as rapamycin and its derivatives may offer new opportunities for therapy. In this review we describe this group of inherited and developmental disorders and discuss recent progress in their treatment via mTORC1 inhibition.

Topics: Animals; Antineoplastic Agents; Everolimus; Genetic Diseases, Inborn; Humans; Immunosuppressive Agents; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Mutation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Fragile X Syndrome; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Research; Humans; Immunosuppressive Agents; Losartan; Marfan Syndrome; Mice; Neurofibromatoses; Sirolimus

We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood stem cells from matched related donors (MRD), 4 patients received peripheral blood stem cells from matched unrelated donors (URD), 4 patients received hematopoietic stem cells from umbilical cord blood donors (UCB), and 2 patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with 3 days of fludarabine and 200 cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and 2 additional days of fludarabine along with 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplantation immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B cell, and natural killer cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients (1 URD recipient and 1 UCB recipient) rejected the donor graft and 1 MRD recipient relapsed with myelodysplastic syndrome after transplantation. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones.

Topics: Adolescent; Adult; Allografts; Antineoplastic Agents; Bone Marrow Transplantation; Child; Cord Blood Stem Cell Transplantation; Female; Follow-Up Studies; GATA2 Transcription Factor; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vidarabine; Whole-Body Irradiation