Conseil de Biosécurité Section Biosécurité et Biotechnologie SECRETARIAT Dr W. Moens REPORT: FIRST GENE THERAPY RELATED DEATH J.C. Dumon, M. Sneyers et W. Moens CONTENTS Chapter I: The clinical case..........................................................................................................2 Introduction.............................................................................................................................2 Introduction.............................................................................................................................2 Partial ornithine transcarbamylase deficiency..........................................................................2 Clinical protocol......................................................................................................................2 Clinical case.............................................................................................................................3 Regulatory aspect....................................................................................................................4 Conclusion..............................................................................................................................4 References...............................................................................................................................5 Information on the death......................................................................................................5 « News » on the Internet......................................................................................................5 Notices and publications of the RAC/FDA..........................................................................7 Literature in appendix..........................................................................................................7 Chapter II: Implications...............................................................................................................8 Introduction.............................................................................................................................8 Clinical case history.................................................................................................................8 Reactions of the investigators and the RAC members to the announcement of this death........9 FDA and RAC Actions..........................................................................................................10 Creation of the Public Health Subcommittee of the US Senate..............................................12 Spontaneous stopping of gene therapy clinical trials.............................................................12 Ethical evaluation of gene therapy..........................................................................................13 Consequences in the USA.....................................................................................................14 References.............................................................................................................................14 Internet references.............................................................................................................14 ‘Paper’ references.............................................................................................................20 Section de Biosécurité et Biotechnologie Rue Juliette Wytsmanstraat, 14 - B 1050 Brussels - BELGIUM Tél: 32-2-642.52.93 | Fax: 32-2-642.52.92 | Email: [email protected] | Web server: http://biosafety.ihe.be 27/06/2000 -P 1/20- Chapter I: The clinical case Introduction Introduction During the month of December, we read in the literature (3-5) and learned via the Internet (1-2) of the death of a patient following the injection of an adenoviral vector, within the framework of a gene therapy clinical trial being run at Pennsylvania University. The Service of Biosafety and Biotechnology (SBB) and the Biosafety Council are obliged to issue expert advice regarding the authorisation of new protocols or amendments to the clinical protocols for gene therapy using this type of vector. The SBB thus addressed a letter to the American Recombinant DNA Advisory Committee (RAC) requesting further information about this death. In the absence of a response from the RAC, and despite the intervention of the American Embassy in Brussels, the SBB managed to gather the information available. The present report is a summary of this information. Partial ornithine transcarbamylase deficiency The pathology treated during the trial was partial ornithine transcarbamylase (OTC) deficiency; this is an enzyme of the mitochondrial matrix intervening in the urea cycle. This genetic pathology is a result of a mutation of the OTC gene, which reduces the hepatic production activities of OTC of 80% to 90% in hemizygotes. This hepatic deficiency in OTC develops in early childhood and leads to an accumulation of ammonia in the blood and the brain, leading to fatal hyper ammoniacal encephalopathy when there is no treatment. An accumulation of glutamin in the blood and an abnormally high excretion of urinary orotic acid also accompany the pathology. The standard treatment for this pathology is the administration of L-Citrulline and a strict protein diet. In some cases, a liver transplant can be considered (27). It should be noted that these patients are particularly vulnerable to all nature of infections (17). Gene therapy has recently become a therapeutic approach. Clinical protocol The clinical trial concerned was a phase I trial. It was being carried out at the hospital of Pennsylvania University (General Clinical Research Center) and at the Children’s National Medical Center; the principal investigator was Dr Mark L. Batshaw, co- investigators were the Section de Biosécurité et Biotechnologie Rue Juliette Wytsmanstraat, 14 - B 1050 Brussels - BELGIUM Tél: 32-2-642.52.93 | Fax: 32-2-642.52.92 | Email: [email protected] | Web server: http://biosafety.ihe.be 27/06/2000 -P 2/20- Drs James M. Wilson and Steven Raper. The Recombinant DNA Advisory Committee (RAC) had approved the trial on 4/12/95 under the reference ORDA 9512-139 (28) and ID UPSM- FDR001529. The clinical trial used an adenoviral vector deleted for the gene E1 of the adenovirus (transcription factor necessary for the replication of the adenovirus) and presenting a heat-sensitive mutation for the E2 gene. This vector expresses the human gene of OTC. Doses of 1X108 to 3X109 units of infectious particles/kg (2X1010 to 6X1011 viral particles/kg) were injected into one of the branches of the hepatic artery using a catheter. The particular criteria for including patients stipulated that the pathology be stable for at least one month, that the concentration of ammonia in the blood be lower than 70µM, and that the titre of anti-adenovirus neutralising antibodies be lower than 1280. It should be noted that among the exclusion criteria, it was recommended that patients do not have a viral hepatitis, AIDS or active tuberculosis (28). Clinical case Jesse Gelsinger, a patient aged 18, was the eighteenth patient who was voluntarily presented for inclusion in this clinical trial (14) under the reference OCT.019 (10). The patient received an injection of 3.8X1013 viral particles (3X109 units of infectious particles/kg) on 13 September 1999 (4). Post-injection, the patient rapidly developed a fever of 40°C (13) together with tachycardia, nausea, vomiting, and muscular pain (13). A hepatic impairment occurred (10), associated with a disseminated intravascular coagulation, which was in the process of improving within 48 hours (11). Unfortunately, after two days, the patient went into a coma (9) and developed respiratory distress (ARDS) requiring artificial ventilation (13). In view of the seriousness of the clinical scenario, which was developing, and the fact that the brain was impaired, the clinicians decided to cease artificial ventilation (18). Death was certified 4 days after having received the injection. At the autopsy, infiltration and inflammation of the lungs were observed (18), as well as anoxia of the kidneys and of the brain, with the spleen and the liver also being affected (16). In the bone marrow, there was also an absence of erythrocyte precursor cells, as well as an abnormality in the maturation of the precursor leukocyte lines (10), which could be linked to a viral infection by a parvovirus type B19 (17). The post mortem investigation led by the investigators excluded human error (8), and the specific analysis of the vector lot administered to this patient did not reveal any particular anomaly (10). In conclusion, and according to Dr James Wilson, the patient died from events occurring subsequent to receiving the injection of the vector (8) which generated a violent immune response (7) and an exaggerated inflammatory response (11) altering several organs and leading to death (5). Section de Biosécurité et Biotechnologie Rue Juliette Wytsmanstraat, 14 - B 1050 Brussels - BELGIUM Tél: 32-2-642.52.93 | Fax: 32-2-642.52.92 | Email: [email protected] | Web server: http://biosafety.ihe.be 27/06/2000 -P 3/20- Regulatory aspect As stipulated in the appendix M-VII-C of the Guidelines for research involving recombinant DNA molecules: May 1999 (24) published by the National Institute of Health (NIH) of the USA, the investigators of this clinical trial reported the death to the local Institutional Review Board, to the Institutional Biosafety Committee, to the NIH Office