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Purine nucleoside phosphorylase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Definitive treatment can be achieved by means of bone marrow transplantation. Transfusion therapy was developed in the management of patients with adenosine deaminase deficiency [34]. In PNP, deficiency transfusion therapy has variously been reported to produce partial improvement or no improvement in immune function [35–38]. In an extensive experience with 100 weeks of erythrocyte transfusion therapy in a boy with PNP deficiency, there was a correction of the elevated level of dGTP in erythrocytes and leukocytes, as well as a substantial increase in serum concentrations of urate and decrease in urinary nucleoside content [7]. The immunologic abnormality was partially reversed. However, the overall results of therapy in this disease have been much less effective than in adenosine deaminase deficiency [39].
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Unless immune reconstitution is provided by treatment, infants with SCID typically die at about 1–2 years of age, mostly due to infections. Recognition of SCID should prompt immediate and aggressive treatment of infections and use of broad antimicrobial prophylaxis, as well as immunoglobulin replacement therapy. Nutritional support is often necessary. The use of live virus immunizations should be strictly avoided, and all blood products should be irradiated and tested for cytomegalovirus before transfusion. Ultimately, treatment and immune reconstitution are based on hematopoietic cell transplantation (HCT). Survival is excellent (greater than 90%) when HCT is performed from HLA-identical donors; however, this option is available only to a minority (less than 15%) of patients. Similarly, good results are obtained when transplantation from HLA-mismatched related donors is performed early in life. Enzyme replacement therapy can be used in patients with adenosine deaminase deficiency, and gene therapy has shown promising results in patients with adenosine deaminase deficiency and with X-linked SCID, although leukemic proliferation due to insertional mutagenesis has been observed in several patients with X-linked SCID following gene transfer.
Inborn errors of metabolism
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Experimental treatments may be tried for some disorders with particularly poor prognoses. One of these is enzyme replacement by bone marrow transplantation, but the results have sometimes been disappointing and it is not without its own complications. Insertion of the missing or defective gene is being attempted for disorders such as adenosine deaminase deficiency. However, for many disorders there is, at the time of writing, still no treatment unless they respond to one of the measures listed above.
Gene therapy for inherited retinal diseases: progress and possibilities
Published in Clinical and Experimental Optometry, 2021
Monica L Hu, Thomas L Edwards, Fleur O’Hare, Doron G Hickey, Jiang-Hui Wang, Zhengyang Liu, Lauren N Ayton
Gene therapy has been explored for a myriad of therapeutic applications. In 1990, the first gene therapy trial commenced in two children with adenosine deaminase deficiency leading to severe combined immunodeficiency, and used white blood cells modified ex vivo to express the deficient adenosine deaminase gene.13 Later, safety issues were indelibly highlighted in 1999 when a fatal immune reaction to an adenovirus vector resulted in the first death of a gene therapy trial patient. Further investigations proceeded with caution and by 2003, China was the first to approve an ex vivo gene therapy product for commercial use—Gendicine (SiBiono GeneTech, China), an adenovirus vector to treat head and neck squamous cell carcinoma.13 Thereafter, the European Union in 2012 approved alipogene tiparvovec (Glybera, uniQure, Netherlands), a recombinant adeno-associated virus for the treatment of familial lipoprotein lipase deficiency.14 In 2017, the US Food and Drug Administration (FDA) approved its first gene therapies: tisagenlecleucel (Kymriah, Novartis, USA), a chimeric antigen receptor T-cell immunotherapy for acute lymphoblastic leukaemia,15 and later voretigene neparvovec (Luxturna, Spark Therapeutics, USA), an adeno-associated virus vector carrying the RPE65 gene for RPE65-associated Leber congenital amaurosis. Luxturna represents a major milestone in ocular gene therapy advancement and was also recently registered by the Australian Therapeutic Goods Association in August 2020, becoming the first approved in vivo gene therapy in Australia.
Phagocytosis: Phenotypically Simple Yet a Mechanistically Complex Process
Published in International Reviews of Immunology, 2020
The receptor downregulation and recycling at the late endosome are supported by CORVET (class C core vacuole/endosome tethering), which is a tethering complex and promotes fusion of Rab5-positive membranes [310]. CORVET binds to SNAREs and Rab5/Vps21-GTP to perform this action. The GEF Vps9 supports the tethering via CORVET, but Msb3, the Vps21-GAP, inhibits it [310,311]. The CORVET and HOPS complexes are also present in mammals. VPS11 serves as a molecular switch within the shared CORVET and HOPS complex through binding to either CORVET-specific TGFBRAP1 or HOPS-specific VPS39/RILP. This binding allows selective targeting of these tethering complexes to early or late endosomes to time fusion events in the endo/lysosomal pathway [312]. The transient receptor potential mucolipin 1 (TRPML1/MCOLN1, a lysosomal Ca2+ channel) along with PI-3,5-bisphosphate (PtdIns(3,5)P2) also plays a significant role in the maturation of phagosome or phagolysosome formation [313,314]. The inhibition of TRPML1 in response to the accumulated adenosine during adenosine deaminase deficiency in lysosomes is associated with severe combined immunodeficiency disease [315]. The loss of TRPML1 induces the cytosolic leakage of cathepsin B (CatB) and thus the induction of apoptotic cell death among immune cells [316].
CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives
Published in Expert Review of Clinical Immunology, 2019
Tabata T. França, Lucila A. Barreiros, Basel K. al-Ramadi, Hans D. Ochs, Otavio Cabral-Marques, Antonio Condino-Neto
Gene therapy has been intensively investigated in the last 15 years as a curative treatment for PID patients without a bone marrow donor [110]. Clinical trials of gene therapy were conducted for the treatment of Adenosine deaminase deficiency (ADA deficiency), X-SCID, CGD, and WAS [111]. The main advantages of gene therapy over standard allogeneic hematopoietic stem cell transplantation (HSCT) are the possibility of ‘low-dose’ or ‘reduced-intensity’ conditioning regimens, as well as the absence of adverse events related to GVHD since the patient’s own bone marrow cells are ‘edited’ and returned to the patient as an autologous cellular product [110]. However, the efficacy of gene therapy has been counterbalanced by the occurrence of insertional oncogenesis [110,112]. Gene therapy for CD40L deficiency has not yet been introduced clinically, but preclinical models are under development [113,114]. Correction of CD40L deficiency by gene transfer in mice improves defective humoral and cellular immune functions. However, these initial efforts caused thymic lymphoproliferative diseases due to the experimentally induced constitutive expression of CD40L, which under physiologic conditions, strict requires regulation of endogenous gene expression [92].