CliniGene - NoE

X-SCID-SAEs

« X-linked-SCIDs SAE » - UK cases

Message released by the investigators - December 2007

Click here to download the .pdf

 

 Scientific papers

Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.

Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von Kalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL, Levinsky RJ, Ali RR, Kinnon C, Thrasher AJ - Lancet. 2004 Dec 18-31;364(9452):2181-7. (PMID: 15610804)

 

Information and Reports from European and US-scientific societies

Joint "ESGCT/ CliniGene/ Concert Commentary re. Serious adverse event UK SCID-X1 gene therapy trial". - December 2007 (link to the .pdf)

 

«X-linked-SCIDs SAE » - French cases

This section gathers and provides Internet-links to a set of documents which are being considered as reference following the occurrence of the first two cases of leukemias in two X-linked-SCID patients among a total of 12 patients treated with retrovirally transduced CD34+ bone-marrow autologous cells. Eight patients are currently doing well without additional treatment. One child has well-responded to the treatment of his leukemia and currently is in complete remission. The other survived the monoclonal proliferation during more than 20 months but could not be cured despitea successful engrafment of allogenic bone-marrow transplantation and a treatment with a monoclonal antibody specific to the junction/integration. The mechanism accounting for the two leukemia cases is treatment-related insertional oncogenesis.

A third case of leukemia has been released. The mechanism of this malignant proliferation is under investigation. Biological tests are currently underway. See Jan 24th press release from the french AFSSAPS : http://afssaps.sante.fr/ang/indang.htm

 

Scientific papers

Hot spots of retroviral integration in human CD34+ hematopoietic cells.

Cattoglio C, Facchini G, Sartori D, Antonelli A, Miccio A, Cassani B, Schmidt M, von Kalle C, Howe S, Thrasher AJ, Aiuti A, Ferrari G, Recchia A, Mavilio F. - Blood. 2007 Sep 15;110(6):1770-8. (PMID: 17507662)

Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo.

Schwarzwaelder K, Howe SJ, Schmidt M, Brugman MH, Deichmann A, Glimm H, Schmidt S, Prinz C, Wissler M, King DJ, Zhang F, Parsley KL, Gilmour KC, Sinclair J, Bayford J, Peraj R, Pike-Overzet K, Staal FJ, de Ridder D, Kinnon C, Abel U, Wagemaker G, Gaspar HB, Thrasher AJ, von Kalle C. - J Clin Invest. 2007 Aug;117(8):2241-9.(PMID: 17671654)

Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy.

Deichmann A, Hacein-Bey-Abina S, Schmidt M, Garrigue A, Brugman MH, Hu J, Glimm H, Gyapay G, Prum B, Fraser CC, Fischer N, Schwarzwaelder K, Siegler ML, de Ridder D, Pike-Overzet K, Howe SJ, Thrasher AJ, Wagemaker G, Abel U, Staal FJ, Delabesse E, Villeval JL, Aronow B, Hue C, Prinz C, Wissler M, Klanke C, Weissenbach J, Alexander I, Fischer A, von Kalle C, Cavazzana-Calvo M. - J Clin Invest. 2007 Aug;117(8):2225-32.(PMID: 17671652)

Real-time definition of non-randomness in the distribution of genomic events.

Abel U, Deichmann A, Bartholomae C, Schwarzwaelder K, Glimm H, Howe S, Thrasher A, Garrigue A, Hacein-Bey-Abina S, Cavazzana-Calvo M, Fischer A, Jaeger D, von Kalle C, Schmidt M. PLoS ONE. 2007 Jun 27;2(6):e570. (PMID: 17593969)

Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque.

Seggewiss R, Pittaluga S, Adler RL, Guenaga FJ, Ferguson C, Pilz IH, Ryu B, Sorrentino BP, Young WS 3rd, Donahue RE, von Kalle C, Nienhuis AW, Dunbar CE. - Blood. 2006 May 15;107(10):3865-7. (PMID: 16439674)

Gene therapy: therapeutic gene causing lymphoma.

Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM. Nature. 2006 Apr 27;440(7088):1123. (PMID: 16641981)

Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1.

Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Lüthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. - Nat Med. 2006 Apr;12(4):401-9. (PMID: 16582916)

Genotoxicity of retroviral integration in hematopoietic cells.

Nienhuis AW, Dunbar CE, Sorrentino BP. Mol Ther. 2006 Jun;13(6):1031-49.

Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis.

Modlich U, Kustikova OS, Schmidt M, Rudolph C, Meyer J, Li Z, Kamino K, von Neuhoff N, Schlegelberger B, Kuehlcke K, Bunting KD, Schmidt S, Deichmann A, von Kalle C, Fehse B, Baum C. Blood. 2005 Jun 1;105(11):4235-46. (PMID: 15713797)

Failure of SCID-X1 gene therapy in older patients.

Thrasher AJ, Hacein-Bey-Abina S, Gaspar HB, Blanche S, Davies EG, Parsley K, Gilmour K, King D, Howe S, Sinclair J, Hue C, Carlier F, von Kalle C, de Saint Basile G, le Deist F, Fischer A, Cavazzana-Calvo M. - Blood. 2005 Jun 1;105(11):4255-7. (PMID: 15687233)

Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trial.

Schmidt M, Hacein-Bey-Abina S, Wissler M, Carlier F, Lim A, Prinz C, Glimm H, Andre-Schmutz I, Hue C, Garrigue A, Le Deist F, Lagresle C, Fischer A, Cavazzana-Calvo M, von Kalle C. - Blood. 2005 Apr 1;105(7):2699-706. (PMID: 15585650)

LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

S. Hacein-Bey-Abina et al, Science 2003; 302 : 415-19

Gene Therapy-New challenges ahead

D.A. Williams & C. Baum, Science 2003; 302 : 400-1

Gene Therapy Insertional Mutagenesis Insights.

Utpal Davé, Nancy A. Jenkins, Neal G. Copeland, Science 2004 ; 303 : 333

Activation of the T-cell Oncogene LMO2 after Gene Therapy for X-linked Severe Combined Immunodeficiency.

Matthew P. McCormack and Terence H. Rabbitts, NEJM 2004 : 350 : 913-22

Chance or necessity? Insertional mutagenesis in gene therapy and its consequences.

Baum C, von Kalle C, Staal FJ, Li Z, Fehse B, Schmidt M, Weerkamp F, Karlsson S, Wagemaker G, Williams DA, Mol Ther. 2004 Jan;9(1):5-13.

LMO2 and gene therapy for severe combined immunodeficiency.

Fischer A, Abina SH, Thrasher A, von Kalle C, Cavazzana-Calvo M., N Engl J Med. 2004 Jun 10;350(24):2526-7; author reply 2526-7.

American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells.

Kohn DB, Sadelain M, Dunbar C, Bodine D, Kiem HP, Candotti F, Tisdale J, Riviere I, Blau CA, Richard RE, Sorrentino B, Nolta J, Malech H, Brenner M, Cornetta K, Cavagnaro J, High K, Glorioso J; American Society of Gene Therapy (ASGT), Mol Ther. 2003; 2:180-7

 

Official positions from European and US-scientific committes acting as advisory bodies to competent authorities

Title : « 3rd complication case in DICS X gene therapy clinical trial» Press release Jan 24, 2005

Source : French medicines Evaluation Agency-AFSSAPS

Title : « Report from the January ad hoc meeting » May 2003

Source : CPMP-Gene Therapy Expert Group (GTEG)

Title : « Outcome of the RAC meeting and Updated advice to investigators regarding adverse events in the X-SCID gene transfer trial » March 2003

Source : Director of the NIH Office of Biotechnology Activites

Title : « Recommandations of the GTAC/CSM working party on retroviruses » April 2003

Source : Gene Therapy Advisory Committee (GTAK-United Kingdom)

 

Information and Reports from European and US-scientific societies

Source : New statement of the EGSCT board on the most recent case of leukemia in the first X-SCID trial (May 2007).

Title :4th case of leukemia in the first SCID-X1 gene therapy trials, and the diversity of gene therapy

Source : European Society of Gene Therapy (ESGT)

SCID Gene Therapy in France on Clinical Hold Due to Diagnosis of a Third Case of Lymphoproliferative Disorder, February 1, 2005

« Positional statement. Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID) » January 2003

« Positional statement. Annual meeting of the ESGT. French gene therapy group reports on the adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID) » October 2002

« Statement. Adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency disease (X-SCID) » October 2002

Source : American Society of Gene Therapy (ASGT)

« Report from the ASGT Ad Hoc Committee on Retroviral-mediated Gene Transfer to Hematopoietic Stem Cells » April 2003

Source: gene Therapy Safety Group

GTSG-vector integration patterns CRSD database (CRSD for Cooperative Risc Score Database; RISC for Retroviral Insertion Site in Chromosome)