Adenosine-Deaminase (ADA) Inadequacy.


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Protein REPLACEMENT THERAPY WITH BOVINE ADA (PEG-ADA). Rectification of metabolic abnormalities.Variable rebuilding of invulnerable capacities, with 20% non responders >50% still on IVIG.Last overview (Hershfield, ESID 2002) general survival 83% (n=113) (73% including patients who experienced BMT).10% created killing antibodies.Autoimmune disorders in 5 patients (lethal in 3). .
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Slide 1

Adenosine-Deaminase (ADA) Deficiency ADA is dependable quality in ~20% SCID. Regularly lethal, if untreated, because of diseases. It was the principal type of SCID where: 1. hereditary cause was distinguished (1972), 2. capable quality was cloned (1983), 3. quality treatment was drawn closer (1990), 4. compelling treatment (PEG-ADA) other than HSCT was produced (1990). PEG-ADA compound substitution treatment: 1. FDA affirmed vagrant medication (1990), 2. Bi-week after week I.M., 3. Can reestablish, support invulnerability, 4. Costly ($200-500,000/yr).

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ENZYME REPLACEMENT THERAPY WITH BOVINE ADA (PEG-ADA) Correction of metabolic variations from the norm. Variable rebuilding of resistant capacities, with 20% non responders >50% still on IVIG. Last overview (Hershfield, ESID 2002) general survival 83% (n=113) (73% including patients who experienced BMT). 10% created killing antibodies. Immune system disorders in 5 patients (lethal in 3).

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1,600 Lower 5 th %ile of typical range Absolute CD3+ T Lymphocyte Count (/mm 3 ) 1,200 800 Years on PEG-ADA 6 11 400 6 5 9 10 9 4 8 0 Pre-PEG-ADA Maximal Most Recent Absolute CD3+ T Lymphocyte Counts In 9 ADA (- ) SCIDs on PEG-ADA 4-11 Yrs Chan … Kohn MS in Prep.

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Bone Marrow Transplantation for ADA-SCID HLA-indistinguishable kin BMT (treatment of decision) Survival 75-90%. Neurological and behavioral adjustments saw in the long haul development. Non HLA-indistinguishable BMT Without molding (haplo): 33% engraftment (n=15) (Buckley et al., exhibited at ESID 2002). With molding: general survival 23% (n=29) (EBMT/ESID registry, Antoine et al., Lancet, 2003, 361:553-560). General survival at Great Ormond Street Hospital (B. Gaspar/A. Thrasher), introduced at EBMT, 2004 HLA-id kin/family giver (84%) (n=13) Matched random benefactor or UCB (half) (n=4) Haploidentical contributor (23%) (n=13 )

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Survival after HLA - befuddled Bone Marrow Transplantation for SCID (EBMT/ESID registry, Antoine et al., Lancet, 2003, 361:553-560) ADA-SCID MUD + haploidentical 23% SCID T-B+ (counting X-SCID) MUD 66% Haploidentical 50%

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Early ADA Gene Therapy Trials # of patients T cells Blaese et al. 1993 2 Bordignon et al. 1992 6* CD34+ cells Bordignon et al. 1992 2* Hoogerbrugge et al. 1992 3 Kohn et al. 1993 3 * same patients

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1 st C H L A/N I H ADA Gene Transfer Trial In 1993, umbilical rope blood was gathered from three ADA-lacking SCID neonates. CD34+ cells were secluded and transduced with the human ADA cDNA by culture for 3 days with the LASN retroviral vector and IL-3/IL-6/SCF. The cells were reinfused I.V. on day 4 of life, without earlier cytoreduction. Treatment with PEG-ADA was started.

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Frequency of Gene-Containing Leukocytes Measured Using Semi-Quantitative PCR PEG-ADA (U/kg/wk) UPN #ADA101 X=gran; = PBMC; M=monocytic; T= T cell; B= B cell Months after birth Kohn et al, Nat Med 4:775-780, 1998 .

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Patient 1 Patient 2 1 9 48* 53 63 80 94 28 32 48* 49 88 28 32 48* 49 94 ° 48 64 72 80 PBMC CD 3+ CD 13/14 PBMC LAM-PCR examination of PBMC, T cells and myeloid cells From: Schmidt et al., Nat Med. 2003; 9(4):463-8

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Summary Schmidt et al., Nat Med. 2003; 9:463-8 LAM-PCR uncovered the steady nearness of an overwhelming vector integrant in T and myeloid cells in the course of recent years. Lymphocyte clones developed from fringe blood 8 years after neonatal CD34+ cell quality transduction demonstrated that: a single pre-thymic stem or ancestor cell accounted for the larger part of quality stamping in polyclonal T cell production.

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Frequency of Gene-Containing Leukocytes Measured Using Semi-Quantitative PCR PEG-ADA (U/kg/wk) UPN #ADA101 X=gran; = PBMC; M=monocytic; T= T cell; B= B cell +11 yrs ↓ X ↑ +11 yrs Months after birth Kohn et al, Nat Med 4:775-780, 1998 .

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2 nd C H L A/N I H ADA Gene Transfer Trial Study parameters: 1. Stage 1 contemplate 2. 10 patients - must be on PEG-ADA E.R.T. 3. ADA-lacking SCID neonates or kids 4. Target cell: CD34+ cells from UCBC (neonates) or BM (kids) 5. Quality exchange technique: Ex vivo transduction with MLV-based RV in GALV-pseudotype utilizing SCF/MGDF/F3L on retronectin, sans serum. 6. Staged withdrawal of PEG-ADA following 1 year, if quality checking present. 7. 2 year dynamic stage development.

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2 nd C H L A/N I H ADA Gene Transfer Trial IND Application, Aug. 1999 IND Approval 2001 4 patients enlisted, Aug 2001 – Jan 2002 UPN Age (y/o) CD34+/kg % PCR+ CFU 201C 15 0.7 12* 202N 5 13.3 50 203N 20 1.3 1 204C 4 2.0 20 * GcSap vector just

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ADA 201C ADA 202N MND - PBMC MND - PMN GC-sap - PBMC ADA 204C ADA 203N GC-sap - PMN ADA Vector Marking 15 y/o 5 y/o # Proviral Copies/Cell 4 y/o 20 y/o Months Post-Infusion

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Clinical Trial of Gene Therapy for ADA-Deficient SCID in Italy Aiuti et al. (Milan). Science 296:2410-2413, 2002 . Two ADA-insufficient SCID given busulfan (4/kg) before BM mixture ("non-myeloablative molding"). Not treated with PEG-ADA treatment. Resistant reconstitution by 6 months. Immune system microorganisms quality set apart at 100% Myeloid cells quality set apart at 7-12%. - - - - - 4 more treated from that point forward, with great invulnerable recuperation

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ADA-SCID quality treatment: the Milan trial + 6 + 6 H SC - P t A g e at tr e atm e nt C D 34 ce ll s (x10 )/K g C D 34 ce ll s (x10 )/K g c ol l e cte d i nf u s e d P t1 7 4 . 1 8 . 6 P t2 3 0 1 . 1 0 . 9 P t3 1 2 3 . 5 . 4 P t4 2 4 . 7 3 . 7 P t5 1 9 7 . 7 9 . 4 P t6 5 4 1 0 . 2 9 . 1 (Aiuti et al. Science, 2002, 296:2410-3 and unpublished information)

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T-cell R econstitution in early stage: correlation of SCID trials X SCID X-SCID ADA-SCID T cells/microl 0 2 4 6 Months of development (Aiuti et al. Science, 296:2410-3 2002 and unpublished information) ( Hacein-Bey et al. Science, 2003, 302:415-9)

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2 nd C H L A/N I H ADA Gene Transfer Trial IND Application, Aug. 1999 IND Approval 2001 4 patients selected, Aug 2001 – Jan 2002 Clinical Hold, Sep. 2002 Clinical Hold lifted Dec 2003 IND changes, incl. Busulfan, PEG-ADA withdrawal, age and cell dosage constrain, last endorsement: Jan 2005 Clinical Hold, Jan. 2005

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ADA (- ) SCID: Summary PEG-ADA palliative, however invulnerable capacity is beneath ordinary Poor result with haplo-BMT No unfriendly occasions in no less than 18 subjects, some with retroviral-exchanged quality present >10 years Good result from quality treatment in Milan examine, utilizing Busulfan and no PEG-ADA

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