Gene therapy SCIDS

Howe et al. 2008). Of note, more than 30 other severely ill patients with two types of SCID have received therapeutically effective gene therapy without clinical or molecular evidence of major side effects in prolonged follow-up. 

Aiuti A, Vai S, MorteUaro A, Casorati G, Ficara F, Andolfi G, Ferrari G, Tabucchi A, Carlucci F, Ochs HD, Notarangelo LD, Roncarolo MG, Bordignon C (2002b) Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 8 423 25... 

The theoretical complications posed by random chromosomal integration became a medical reality in 2002, when two children who had received retroviral-based gene therapy 2 years previously developed a leukaemic-like condition. The initial clinical trial aimed to treat X-linked severe combined immunodeficiency (SCID-X1), a hereditary disorder in which T-lymphocytes and NK cells in particular do not develop, due to a mutation in the gene coding for the yc cytokine receptor subunit. The clinical consequence is near abolition of a functional immune system. 

The trial entailed retroviral-mediated ex vivo transduction of haematopoietic stem cells from 10 young SCID-X1 sufferers, with subsequent re-infusion of the treated cells. A marked and prolonged clinical response in which the condition was essentially reversed was observed in 9 out of the 10 patients. The prolonged response was likely due to the transduction of pluripotent progenitor cells with self-renewal capacity (Chapter 10). However, the two youngest patients (1 and 3 months old at the time of treatment) developed uncontrolled proliferation of mature T-lymphocytes 30 months and 34 months after gene therapy respectively. 

Another early genetic disease for correction by gene therapy was SCID. One form of this disease is caused by a lack of adenosine deaminase (ADA) activity. ADA is an enzyme that plays a central role in the degradation of purine nucleosides (it catalyses the removal of ammonia from adenosine, forming inosine, which, in turn, is usually eventually converted to uric acid). This leads to T- and B-lymphocyte dysfunction. Lack of an effective immune system means that SCID sufferers must be kept in an essentially sterile environment. 

The first gene therapy trial was conducted in September 1990. A 4-year-old girl with SCID (an inherited immune disorder disease, otherwise known as the bubble boy syndrome) was treated in Cleveland, Ohio. She is doing well some 10 years after the treatment. A second girl with the same disorder underwent gene therapy and she too continues to do well. 

Currently, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

Gene therapy offers another potential avenue to fix the defective gene. The therapy itself is by no means straightforward. In a French gene therapy trial, three boys with SCID were treated using retrovirus-based gene therapy. They later developed cancer and one died of leukemia. Reviews showed that the retrovirus inserted near oncogenes and promoted development of cancer. 

Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LM02-associated clonal T cell proliferation in two patients after gene therapy for SCID-Xl. Science 2003 302(5644) 415 19. 

Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, produces severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successfiil cures. 

Larochelle A, Vormoor J, Hanenberg H, et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow implications for gene therapy. Nat Med. 1996 2 1329-1337. 

In 2000, French researchers announced the first gene therapy cure in nine children with X-linked severe combined immune deficiency (X-SCID). This rare condition is caused by the inherited loss of a protein that is part of the docking site for critical immune system signal proteins. Because of this defect, children with X-SCID have no mature, working lymphocytes—critical immune system cells. 

L Severe combined immunodeficiency (SCID) syndromes are excellent models for gene therapy because of the genetic basis of these disorders and significant advances in the technology to transfer therapeutic genes into hematopoietic precursor cells. For all these reasons, which of the following syndromes represents an ideal candidate for gene therapy ... 

L C. SCID-Xl (yC deficiency) is an optimal model for gene therapy because there is little yC gene transcription regulation yC expression is ubiquitous and constitutive among different hematopoietic Uncages and yC exerts no autonomous function. 

Blaese, R.M. (1995). T-lymphocyte-directed gene therapy for ADA-SCID Initial trial results after 4 years. Science, 270, 475 180. 

Cavazzana-Calvo, M. (2000). Gene therapy of human severe combined immune deficiency (SCID)-Xl disease. Science, 288, 669-672. 

San Raffaele Telethon Institute for Gene Therapy is developing an adenosine deaminase transduced hematopoietic stem cell therapy for the potential intravenous treatment of adenosine deaminase deficiency in severe combined immunocompromised individuals (ADA-SCID). 

Using the optimal protocol combination of T/F/S and IL-3 that was developed from a series of preclinical studies (outlined above), autologous HSC gene therapy for ADA-SCID was performed in combination with nonmyeloablative conditioning (2 mg/kg/day of busulfan) in two patients (aged 7 months [Ptl], and two years and 6 months [Pt2], respectively) [515130], [515136], [607777]. 

Pioneering studies have demonstrated the potential of gene therapy for the treatment of inherited hematopoietic diseases [440300], and particularly for ADA-SCID [470017], [470024], [666662], [666664], [666665]. However, vector design, gene transfer protocols and inadequate engraftment and expansion of genetically engineered cells limited the success of earlier studies [206054], [657269], [657273], [668669]. 

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