The Wire

Abstract

Science wire

SINs are good for integration

Insertional mutagenesis occurs when a viral vector integrates into the host genome adjacent to a cellular protooncogene and triggers oncogenesis. Compared with lentiviral (LV) vectors, γ-retroviral (γRV) vectors display a greater potential for inducing oncogenic adverse events by insertional mutagenesis and are therefore considered more genotoxic. In their latest work,¹ Montini, Cesana, and colleagues at the San Raffaele-Telethon Institute for Gene Therapy examine the contribution of various genetic elements of LV and γRV vectors to insertional mutagenesis. The authors create a panel of chimeric vectors by swapping genetic elements between LV and γRV vectors. Genotoxicity of the chimeric vectors was then evaluated in vivo, using a well-established tumor-prone animal model. Using this approach the authors demonstrate that transcriptionally active long terminal repeats (LTRs) are major determinants of insertional mutagenesis. Specifically, they show that LV vectors with chimeric γRV LTRs result in a strong dose-dependent acceleration of tumor onset in the Cdkn2a^−/− hematopoietic stem/progenitor cell (HSPC) transplantation mouse model. Interestingly, the authors compare the genotoxicity of vectors with matched active LTRs and find that an approximately 10-fold higher integration load of LV is required to approach the same oncogenic risk as γRVs; this is explained as being a function of γRV's preferential integration bias for cancer genes. Importantly, the authors demonstrate that improvements in vector design, such as self-inactivating (SIN) LTRs, greatly reduce the genotoxic risk in both LV and γRV vectors. “This is a very important and timely study,” states Dr. Peter Cherepanov of the Imperial College of London. “Perhaps the next step would be to develop retroviral vectors with modified integration site preferences.” Cherepanov notes that “the lentiviral integration mechanism, which is relatively well understood, might allow design of vectors that preferentially integrate within safer genomic loci.” (sk)

Montini

et al. 2009. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J. Clin. Invest., 119:964–975.

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Regulatory wire

The U.K. Department of Health, in collaboration with other regulator agencies, has released its Interim UK Regulatory Route Map for Stem Cell Research and Manufacture. This document is intended as a reference tool for those who wish to develop a program of stem cell research and manufacture, ultimately leading to clinical application. A copy of the map can be found at: http://www.advisorybodies.doh.gov.uk/genetics/gtac/InterimUKSCroutemap120309.pdf

On June 23, 2009 the NIH's Recombinant DNA Advisory Committee (RAC) will be convening a 1-day meeting in Arlington, Virginia called “Synthetic Nucleic Acids and the NIH Guidelines for Research Involving Recombinant DNA Molecules” to discuss whether current RAC guidelines should be broadened to include basic and clinical research involving nonreplicating synthetic molecules (e.g., antisense RNA and RNAi). According to RAC members Dr. Hildegund Ertl and Dr. Jacqueline Corrigan-Curay, the purpose of this one-time meeting is “to allow further opportunity for discussion and public input on the proposed revisions to the NIH guidelines for synthetic nucleic acids.” A complete agenda of the meeting can be found at: http://oba.od.nih.gov/rdna/rdna.html

Industry wire

Targeted Genetics (Seattle, WA)

According to CEO Susan Robinson, if Targeted Genetics is unable to improve its financial situation by the end of June 2009 it will “begin the process of ceasing operations, seeking bankruptcy protection or otherwise winding up our business.” The announcement was made in a conference call as part of the company's release of its first-quarter financial results. Since its founding in 1992, Targeted Genetics has developed no marketed products and has accrued a $322.7 million deficit.

Pfizer (New York, NY)

The drugmaker announced that it will be investing $100 million in its international stem cell development program, Pfizer Regenerative Medicine. This cash injection, according to Business Week, is the single highest funding amount that the stem cell discipline has ever received from the corporate sector.

Oxford BioMedica (Oxford, UK)

French pharmaceutical giant Sanofi-Aventis has established a $51 million collaborative deal with Oxford BioMedica. The agreement covers four of BioMedica's lentiviral vector-based products: RetinoStat for wet age-related macular degeneration, StarGen against Stargardt disease, UshStat for Usher syndrome type 1B, and EncorStat for corneal graft rejection. Under terms of the collaboration, Oxford BioMedica will be responsible for continued preclinical and phase I/II development of the products; Sanofi-Aventis will have an exclusive option to worldwide development and commercialization of the products. According to company projections, all four products will be in phase I/II development within 3 years. BioMedica reports that this new agreement has improved its financial position significantly, and that it now has enough cash to support operations into 2012.

Applied Genetic Technologies Corporation (Alachua, FL)

Applied Genetic Technologies Corporation (AGTC) has closed on an $11.8 million venture financing deal that includes InterWest Partners, Intersouth Partners, and MedImmune Ventures, Inc. as investors. The investment funds will be used by AGTC to complete the next phase in human clinical trials for its AAV-based gene therapy treatments for α₁-antitrypsin deficiency and Leber's congenital amaurosis, and preclinical development of gene therapy treatment for achromatopsia, a form of daytime blindness.