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Death prompts a review of gene therapy vector

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Case study and analysis of Targeted Genetics' adeno-associated virus, tgAAC94. Includes overview of clinical trial design, FDA action, NIH investigation, and outcomes surrounding the death of a patient enrolled in the investigational trial.

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Death prompts a review of gene therapy vector

  1. 1. Death Prompts a Review of Gene Therapy Vector Case Study and Analysis Prepared by: Lindsay Meyer SC30001 – Bioinformatics 31 October 2007 Page 1 of 6
  2. 2. Introduction to Gene Therapy Gene therapy is the term given to clinical algorithms that deliver DNA sequences to cells with the goal of preventing, treating, or curing diseases. Preliminary efforts in the field were aimed at delivering a normal copy of missing or defective genes. Gene delivery now encompasses a wider array of functions including encoding therapeutic proteins, silencing disease-causing genes, vaccinating against bacterial genes, stimulating tissue regeneration, and catalyzing apoptosis.1 For eight years gene therapy has coasted along without scientific headwind. Red flags have long been raised among ethics groups about the morality of manipulating the human genome to improve or enhance the human species,2 but in its relatively short history, gene therapy has been a mostly benign field of experimentation. Until mid 2007, just one patient death had been recorded as a result of gene therapy. Three others had acquired leukemia. About Targeted Genetics Targeted Genetics (“TGEN”) was founded in Seattle and became a publicly traded company in 1994. The firm focuses its research efforts on development of an HIV vaccine and as novel treatments for congestive heart failure, Huntington’s disease and hyperlipidemia. TGEN’s most promising drug candidate seeks to revolutionize the treatment of rheumatoid arthritis (“RA”) by building on the success of Amgen’s ENBREL©. Enbrel is a protein-based treatment engineered to block tumor necrosis factor-alpha (TNF-α) used in RA patients. Among biologics, anti-TNF antibodies are the third largest class of medications. In 2006, Enbrel posted sales of $4.5 billion.3 TGEN relies on a viral vector to modify the transport of TNF-α inhibiting molecules. 1 Targeted Genetics. “About Gene Therapy.” http://www.targen.com/Research-Development_About%20Gene%20Therapy.htm. Accessed 30 October 2007. 2 Caplan, Arthur. “If Gene Therapy is the Cure, What is the Disease?” http://www.bioethics.net/articles.php? viewCat=6&articleId=58. Accessed 30 October 2007. 3 PipelineReview.com. “Top Classes of Biologics With Sales of US $63.8 Billion.” http://www.medicalnewstoday.com/articles/63924.php. Accessed 30 October 2007. Page 2 of 6
  3. 3. Adeno Associated Viruses TGEN’s RA drug candidate is an adeno-associated virus known as tgAAC94. Once injected, the viral vectors move to specified cells (in this case – those in the joints) and alter the DNA sequence, stimulating local production of TNFR:Fc. TNFR:Fc binds to TNF-α and prevents direct contact with the cell membrane. By inhibiting direct binding to the cell surface, TNFR:Fc stops the inflammatory response associated with RA. The proposed benefit of tgAAC94 is a “localized depot” of Enbrel that works for a longer time horizon.4 In Focus: Patient Death Previous to launching human studies, Since initiating clinical trials of the therapy in 2005, 127 patients received first doses of the vector without any serious side effects. Of the seventy 4 Kaiser, Jocelyn. “Death Prompts a Review of Gene Therapy Vector.” Science, Volume 317. 3 August 2007. Page 3 of 6 “A joint effort” Making proteins to stop TNF-α
  4. 4. four patients that received a second dose of tgAAC94, 55 received active doses. On July 24, 2007, four days after developing a severe reaction that was “related in time” to receiving a second injection of tgAAC94, one patient died at the University of Chicago. The FDA halted TGEN’s trial and conducted a preemptive review of 28 other trials involving AAV. The patient death was the first fatality in a trial not studying a life-threatening disease. Speculation and Clinical Hypotheses Several respected medical doctors and scientists weighed in on the issue. TGEN’s own Barrie Carter was the first to stand behind the treatment. He was quick to reference the success of some 500 prior instances of patients safely receiving AAV vector-based therapies. The gene product, TNFR:Fc was cast as an immediate suspect. Because Enbrel suppresses immune response, studies have shown a higher incidence of sepsis and bacterial infections in patients receiving the drug. What separates the TGEN trial from earlier ones is the contingent of patients who received multiple doses. Chris Evans, a molecular orthopedist from Harvard Medical School who is planning a test of gene therapy to treat RA, expressed concern that patients who received multiple doses of the vector may have become sensitized to it leading to an adverse reaction.5 The NIH Response When the Recombinant Drug Advisory Committee (“RAC”) of the NIH met on September 17, 2007, they had a lot of business to discuss. On the agenda were several keynote addresses regarding July’s gene therapy death. Jacqueline Corrigan-Curray kicked off the meeting with an overview of AAV vector-based clinical protocols. An overview of RA and the role of TNF inhibitors followed Dr. Curray’s presentation. Eric Matteson, Professor of Rheumatology at the Mayo Clinic provided the clinicians perspective before the case was 5 Kaiser, Jocelyn. “Death Prompts a Review of Gene Therapy Vector.” Science, Volume 317. 3 August 2007. Page 4 of 6
  5. 5. discussed. Two practicing Pathologist’s from the University of Chicago Hospital System presented the patient autopsy data and then five panelists convened to pick apart the case.6 Outcomes Immediately following the RAC meeting on September 17th, TGEN issued a press release. The release noted that “histoplasmosis played a significant role in the patient’s death.”7 Histoplasmosis is a fungal infection that can progress rapidly in patients with weakened immune systems. Many RA patients are undergoing treatment regiments that contribute to a suppressed immune condition, and the patient was receiving a cocktail of other medications. For TGEN’s scientific and investor community, the lack of vector replication and trace amounts of vector DNA in tissues outside the joint eased many concerns that tgAAC94 was directly responsible for the patient’s death. Going forward, TGEN announced that it will continue to collaborate with the FDA, RAC, and academics to complete the investigation. Analysis The completion of the Human Genome Project has left scientists with a near infinite amount of genetic data to catalog and exploit. Advances in biotechnology continue to spur the creation of new, novel therapies. For every ten steps forward, some amount of backtracking will be necessary. The scientific method has proved itself as a useful pedagogy for innovation and testing of new medications. But for a field in its infancy, setbacks always come with a margin of pain and disappointment. With TGEN mostly out of the woods regarding its AAV vector, it’s safe to say that manipulation of DNA to prevent, treat, and cure diseases has experienced great success in the 6 National Institues of Health. 109th RAC Meeting. 17 September 2007. 7 Targeted Genetics Corp. “Targeted Genetics Reports on RAC Review of it’s Phase 1/2 Trial of tgAAC94 for Rheumatoid Arthritis.” http://ir.targen.com/phoenix.zhtml?c=84981&p=irol-newsArticle&ID=1052409&highlight=. Accessed 31 October 2007. Page 5 of 6
  6. 6. last decade. One patient death in eight years is an outstanding track record for a field that has blossomed out of test tubes. The prospects remain bright for gene therapy. The risk-reward profile in applied science is greatly magnified when human lives are test subjects. But as Barrie Carter, TGEN’s Chief Scientific Officer emphasized, “It is critical that we let the clinical trial and scientific process determine the risks and potential of gene therapy before rushing to judgment and hampering the development of what could one day play a significant role in the treatment of serious diseases."8 8 Targeted Genetics Corp. “Targeted Genetics Reports on RAC Review of it’s Phase 1/2 Trial of tgAAC94 for Rheumatoid Arthritis.” http://ir.targen.com/phoenix.zhtml?c=84981&p=irol-newsArticle&ID=1052409&highlight=. Accessed 31 October 2007. Page 6 of 6
  7. 7. last decade. One patient death in eight years is an outstanding track record for a field that has blossomed out of test tubes. The prospects remain bright for gene therapy. The risk-reward profile in applied science is greatly magnified when human lives are test subjects. But as Barrie Carter, TGEN’s Chief Scientific Officer emphasized, “It is critical that we let the clinical trial and scientific process determine the risks and potential of gene therapy before rushing to judgment and hampering the development of what could one day play a significant role in the treatment of serious diseases."8 8 Targeted Genetics Corp. “Targeted Genetics Reports on RAC Review of it’s Phase 1/2 Trial of tgAAC94 for Rheumatoid Arthritis.” http://ir.targen.com/phoenix.zhtml?c=84981&p=irol-newsArticle&ID=1052409&highlight=. Accessed 31 October 2007. Page 6 of 6

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