SCIDS

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Poly(ethylene glycol) (PEG) molecules attached to adenosine deaminase (ADA) have been used in patients exhibiting symptoms of the severe combined immunodeficiency syndrome (SCID) caused by ADA deficiency. The modified enzyme has a plasma half-life of weeks as compared to the unmodified enzyme (minutes) (248). PEG-L-asparaginase has induced remissions in patients with non-Hodgkin s lymphoma (248). However, one disadvantage of PEG-enzyme treatment is its expense, ie, a year s treatment costs about 60,000 (248). 

ADA SCID (adenosine deaminase-defective severe combined immunodeficiency) is a fatal genetic disorder caused by defects in the gene that encodes adenosine deaminase (ADA). 

The consequence of ADA deficiency is accumulation of adenosine and 2 -deoxyadenosine, substances toxic to lymphocytes, important cells in the immune response. 2 -Deoxyadenosine is particularly toxic because its presence leads to accumulation of its nucleotide form, dATP, an essential substrate in DNA synthesis. Elevated levels of dATP actually block DNA replication and cell division by inhibiting synthesis of the other deoxynncleoside 5 -triphosphates (see Chapter 27). Accumulation of dATP also leads to selective depletion of cellular ATP, robbing cells of energy. Children with ADA SCID fail to develop normal immune responses and are susceptible to fatal infections, unless kept in protective isolation. 

The soluiiou of silver nitrate is acidified with dilute uitric scid, boiled so 49 to decompose an v ailvov sulphite that might have been formed, aud the precipitate filtered, washed, etc. 

First MB, Spitzer RL, Gibbon M, et al Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Patient Edition With Psychotic Screen (SCID-I/ P W/ PSY SCREEN) New York, New York State Psychiatric Institute, Biometrics Research, 1997... 

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... 

Bai J, Gorantla S, Banda N, Gagnon L, Rossi J, Akkina R (2000) Characterization of anti-CCR5 ribozyme-transduced CD34-I- hematopoietic progenitor cells in vitro and in a SCID-hu mouse model in vivo. Mol Ther 1 244—254... 

Sanders VJ, Mehta AP, White MG, Achim CL (1998) A murine model of HIV encephalitis xenotransplantation of HIV-infected human neuroglia into SCID mouse brain. Neuropathol Appl Neurobiol 24(6) 461 67... 

A number of per-scids and organic derivatives of hydrogen peroxides are manufactured by Laporte Chemicals Ltd., Luton, England. 

In vivo studies were carried on the aziridinated cyclopent[Z ]indole quinone out before it was discovered that the aziridinyl ring did not participate in DNA alkylation. The results in Fig. 7.22 for the B16 melanoma syngraft model reveal that there was substantial reduction of tumor mass at 3 mg/kg. However, toxicity (animal deaths) became apparent at 5 mg/kg. On the other hand, human lung cancer xenografts in SCID (severe combined immunodeficient) mice were reduced to 50% mass with 3x1 mg/kg doses without any animal deaths. 

The optimal myeloablative preparative regimen is challenging to study because several indications for HCT (e.g., SCID and thalassemia) are rare enough that it is not feasible or is cost-prohibitive to conduct clinical trials that are powered adequately to detect clinically relevant differences. The longterm outcomes of busulfan-cyclophosphamide (BU-CY) and... 

Plett PA, Frankovitz SM, Wolber FM, Abonour R, Orschell-Traycoff CM. Treatment of circulating CD34+ cells with SDF-lalpha or anti-CXCR4 antibody enhances migration and NOD/SCID repopulating potential. Exp Hematol 2002 30(9) 1061-1069. 

Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1 activates the inte-grins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood 2000 95( 11) 3289-3296. 

Blades MC, Ingegnoli F, Wheller SK, et al. Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID Mice. Arthritis Rheum 2002 46(3) 824-836. 

Lapenta C, Spada M, Santini SM, et al. Pertussis toxin B-oligomer inhibits HIV infection and replication in hu-PBL-SCID mice. Int Immunol 2005 17(4) 469-475. 

Arenberg DA, Kunkel SL, Polverini PJ, Glass M, Burdick MD, Stricter RM. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 1996 97(12) 2792-2802. 

Beider K, Nagler A, Wald O, et al. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood 2003 102(6) 1951-1958. 

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

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