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Jul 1, 2010 (Vol. 30, No. 13)

Spotlight on Opportunities & Innovations

BIO Forums Showcase Strategies and Technologies for Overcoming Obstacles

  • Research Spotlight

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    Using a variety of mobile DNA technologies (including piggyBac) and stem cell technologies, Transposagen Biopharmaceuticals produces a variety of research models. TGEM Rat Models in development will reportedly allow for the creation of more complex genetic manipulations such as knockins and conditional mutations. Transposagen also developed TKO™ Knockout Rat Models including the SCID rat, using mobile DNA technology to create a single gene trap insertion.

    “Genomic Data in Clinical Trials: It is Inevitable,” was the title of a presentation by Boris Umylny, Ph.D., from Japan Bioinformatics.

    Although utilization of genomic information in drug development and clinical trials has been slow to take hold, Dr. Umylny believes that in the near future it will play a greater role in predicting adverse reactions, rescuing failed products, and contributing to the design of adaptive clinical trials.

    Driving increased utilization of genomic data are continuing improvements in data-generation techniques that are leading to the $1,000 personal genome, healthcare budget pressures and a move toward outcome-dependent pricing, and FDA support for the collection of genomic data during clinical trials. The evolution toward personalized medicine will require access to personalized genomic information, noted Dr. Umylny. 

    He predicted that one of the main applications of genomic data in clinical trials will for modeling and simulation of pharmacokinetic and pharmacodynamic studies. A key technology challenge is developing the software capability to apply genomic information and the millions of biomarkers involved. Enhancing software capabilities can rely on the purchase of commercial products or accessing public domain options.

    In his presentation “New Methods of Genetic Manipulation and Their Role in Drug Discovery,” Eric Ostertag, M.D., Ph.D., president and CEO of Transposagen Biopharmaceuticals, proposed a solution to the high failure rate plaguing therapeutic candidates in late-stage development. He described the advantages of working with new rat models that more closely represent human physiology, size, and toxicologic responses, compared to traditional mouse models of disease.

    Dr. Ostertag summarized the main approaches for producing genetic alterations in rats—mutagenesis, transgenesis, and the creation of humanized animal models. Among the techniques for mutagenesis is mobile DNA technology, using DNA transposons such as piggyBac or Sleeping Beauty to generate insertional mutations.

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    NuPotential is working to overcome epigenetic barriers. (A) Somatic cells treated with current generation epi-drugs can induce transcriptionally permissive chromatin states (B). Epigenetic redundancy restores chromatin to a closed state, thus limiting reprogramming (C). Novel epi-drug compounds being designed and developed by the firm inhibit epigenetic redundancy and induce expression of pluripotency genes (D).

    Kenneth Eilertsen, Ph.D., CSO of NuPotential, described the company’s approach to overcoming epigenetic barriers that limit somatic cell reprogramming for the development of cell-based therapies. The use of small molecules to reprogram human somatic cells to a pluripotent state is complicated by evidence of epigenetic redundancy/compensation that limits persistent changes in gene expression.

    NuPotential is pursuing the discovery and development of combinations of small molecules capable of inducing expression of pluripotency genes and overcoming mechanisms of epigenetic redundancy. Induction of transcription factor networks can achieve overexpression of genes active in cellular reprogramming, including Oct4, Sox2, and Nanog. Overcoming epigenetic barriers established during cellular differentiation may require the erasure of “epigenetic memory” by replacing transcriptionally repressive histones with transcriptionally permissive histones and demethylating key promoters.

    The company is using RNA interference (RNAi) technology to introduce short hairpin RNA (shRNA)/lentivirus vectors that can knock down epi-gene activity and identify targets for small molecule drugs capable of incapacitating epigenetic redundancy and achieving de-repression of transcriptionally inactive pluripotent genes required for re-differentiation of somatic cells into multiple lineages. It is developing and screening focused compound libraries to discover optimal combinations of small molecules for cellular reprogramming.

    Hiroto Hara, Ph.D., manager of alliance and project promotion at DNAVEC described the company’s PlasmEx™ core platform technology that uses a Sendai virus-based cytoplasmic expression system to generate induced pluripotent stem (iPS) cells, RNA-based vaccines, and therapeutics.

    Genes for cellular reprogramming or vaccine/therapeutic development are transduced into the host cell cytoplasm, where they express the proteins of interest. As the transduction vectors are RNA-based and do not enter the nucleus, there is no risk of recombination with the host genome or of chromosomal damage. The PlasmEx and transgenes can be cleared from cells within a few days using a targeted manipulation. The company plans to introduce the CytoTune™ vector kit for iPS cell generation during 3Q10, it will carry genes for the four Yamanaka reprogramming factors.

    These genes modulate epigenetic factors from the cytoplasm to promote over-expression of iPS-inducing genes. Genes for iPS cell differentiation can also be transduced using PlasmEx. DNAVEC is also developing PlasmEx as a platform for producing genetic vaccines for AIDS and influenza, as well as for gene therapy.

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