Abstract
Industry wire
Clinical Trial wire
Unraveling the Cascade of Events following Retroviral Integration
Moloney murine leukemia virus (MLV)-based vectors were the first retroviral vectors used in clinical trials. 1 An important milestone in their development for clinical gene therapy was reached by the team of Alain Fischer and Marina Cavazzana-Calvo when patients with severe combined immunodefi-ciency (SCID) were treated successfully by ex vivo interleukin-2 receptor γ (IL2RG) gene transfer in autologous hematopoietic stem and progenitor cells (HSPCs). 2 Soon afterward, however, when several patients developed acute T cell leukemia, the risk of insertional mutagenesis by the retroviral vector was reassessed. 3 Indeed, in certain subjects it was shown that overexpression of a proto-oncogene, due to an MLV insertion, apparently led to a clonal expansion causing the leukemia. It was long speculated that the particular course of events was a function of IL2RG or the ex vivo transduction procedure and that other MLV applications may not suffer the same unfortunate safety risk.
A study by Stein and colleagues, published in the February issue of Nature Medicine, illustrates another series of events due to retroviral vector integration associated with adverse events. 4 The authors present the long-term follow-up on two subjects with chronic granulomatous disease (CGD) who received autologous transplantation of HSPCs gene-modified with MLV. X-linked CGD is a rare congenital immunodeficiency with a functional defect in phagocytic neutrophils leading to an inability to fight off bacterial and fungal infections. The authors reported the initial promising results in 2006 that demonstrated good cell grafting and clinical improvement; an overrepresentation of cells with particular insertions were noted. 5 Fifteen and 26 months after gene transfer, the condition of the two subjects worsened significantly with a progressive decline in neutrophils, red blood cells, and platelets; bone marrow myelodysplasia; and a loss of expression of the vector-encoded NADPH oxidase, eventually leading to the death of one patient and a life-saving bone marrow transplant for the other subject.
In their report, Stein and colleagues unravel the molecular events leading up to the serious adverse events. The clonal expansion of cells emerged with a retroviral integration in the MDS1-EVI1 gene locus that progressed to a point of clonal dominance. About 10 months after gene therapy, however, both patients gradually lost expression of the therapeutic transgene in peripheral blood mononuclear cells (PBMCs), which was likely due to CpG methylation of the viral long terminal repeat, which silenced expression. What is remarkable is that 21 and 33 months into the study, the subjects' PBMCs contained a subpopulation of cells that had lost a single copy of chromosome 7, likely due to disrupted centrosome replication due to the EVI1 insertion. This monosomy is known to lead to myelodysplastic syndromes and acute myeloid leukemia. Twenty-seven months after gene therapy the patient died of multiorgan failure due to septic shock. (lhv)
References
Regulatory wire
Government Report on Gene Patents Raises Furor of Industry
The Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS), which is charged with advising the U.S. Secretary of Health and Human Services (HHS) on human health and societal issues raised by the development and use of genetic technologies, has issued its long-awaited report on gene patents. 1 The report, the product of a 5-year process, has stirred up sharp opposition from industry and trade groups, most particularly over the report's recommendations to exempt genes from certain patent claims under the Bayh–Dole Act (BDA).
Before passage of the BDA in 1980, the federal government retained exclusive ownership of federally funded inventions and made these discoveries available through nonexclusive licenses to anyone who wanted to practice them. Except in rare cases, the inventing organization had no right of ownership. As a result, the federal government held title to approximately 28,000 patents; fewer than 5% of these were licensed to industry for the development of commercial products. 1 With the passage of the BDA, U.S. universities, small businesses, and nonprofits gained intellectual property control of their inventions and other property resulting from federal government-funded research. This has resulted in an increase in the commercialization of scientific discoveries. According to the Association of University Technology Managers (AUTM), since passage of the BDA more than 2200 companies have been formed that were based on the licensing of an invention from an academic institution. Moreover, there are more than 1000 products currently on the market that are based on university-licensed discoveries. Nearly 70% of active licenses are in the life sciences. 2
With respect to the discovery of new genes, the SACGHS report recommends a different approach. The SACGHS advises HHS, among other things, to promote the following: (1) “The creation of an exemption from liability for infringement of patent claims on genes for anyone making, using, ordering, offering for sale, or selling a test developed under the patent for patient care purposes” and (2) “the creation of an exemption from patent infringement liability for those who use patent-protected genes in the pursuit of research.” 1 The SACGHS also recommends measures that promote broad licensing practices of gene patents, and enhance transparency of information about genetic patents and licenses. The SACGHS explains that gene patents may stifle innovation because they can lead to restricted use of genetic tests and can make it difficult for researchers to access information about the genes or to use them in research.
In response to the SACGHS recommendations, the Biotechnology Industry Organization (BIO) trade group, along with numerous companies such as Genzyme, Ceregene, Monsanto, and Celera, sent a letter to HHS, urging it to “reject these recommendations and ensure that the fundamentals of the innovation system put in place nearly 30 years ago through the Bayh–Dole Act are preserved.” 3 The signatories argue that the report's recommendations “would chill future investment and innovation in this area, and would unfairly upset the investment-backed expectations of current patent owners and licensees.” 3 (sk)
References
EMA Outlines 2015 Road Map for Science, Medicine, and Health
The European Medicines Agency (EMA) has launched a 3-month public consultation on its Road Map to 2015, coinciding with its 15th anniversary on January 26, 2010.
The new road map focuses on a number of issues that are relevant to academics, clinicians, and companies involved in research and development. For example, the EMA says it needs to face up to the prospect of regulating new and emerging science, such as personalized medicine, nanotechnologies, gene therapy, regenerative medicine, and synthetic biology, as well as advances to streamline nonclinical and clinical development.
The agency says these will bring issues that require careful consideration, including whether the current legal/regulatory framework can deal with potential safety issues, in particular with respect to the benefit–risk evaluation. A working document has been made available online. 1
The road map acknowledges that scientific progress over the next 5 years will be an important driver for change. Building on current experience with advanced therapies including cell therapy, gene therapy, and tissue engineering, the EMA will have to address the new challenges of regulating nanotechnologies, synthetic biology, and regenerative and personalized medicine.
To address this, the agency proposes to consider whether the regulatory framework needs reorganization. The road map also pledges to help tackle the productivity gap in drug development, saying feedback has indicated that both the suboptimal management of the clinical development process by sponsors, as well as new requirements for medicine development, have been identified as important contributing factors. (sk)