The Silent (R)evolution of Polymeric Nucleic Acid Therapeutics

Appendix

Interview Questions for Dr. Ernst Wagner

• 1. What do you think holds the key to your success as a pharmaceutical scientist?

  To learn about biological mechanisms and try to either mimic or inhibit them by chemical means. The molecular program of life—our own material basis—has created amazing solutions for structures and dynamic processes, providing great inspirations for material sciences and developing therapies.

• 2. What do you consider to be your key research accomplishments?

  The development of synthetic virus-like gene delivery systems, by abstracting the highly effective delivery functions from viruses and try to restore them in new synthetic structures. The repertoire of synthetic chemical building blocks is far more diverse in the space of physicochemical properties than natural building blocks (like peptides, lipids, carbohydrates). This diversity makes it possible to design chemical analogues to viral protein functions with much simpler and more accessible structures (for example, simple polycations for nucleic acid condensation, PEG for nanoparticles shielding, hydrophobic structures for membrane destabilization).

• 3. What was the turning point in your career?

  At the age of 28, when I became group leader at the Research Institute of Molecular Pathology in Vienna, diving as chemist into a completely different research environment of world-class disease-focused molecular biology.

• 4. Who are the individuals who most influenced your research career?

  Prof. Christian Noe taught me that not collecting data like a sponge, but understanding the connections and putting them together in a rational model is what is important, as basis for a hypothesis-driven research. Prof. Albert Eschenmoser showed me how to motivate and build a team, to guide with far-sighted vision and a clear program, at the same time providing each team member with freedom to operate and fostering the individual creativity which then fed back into the team’s success. Prof. Max Birnstiel as a pioneer in novel research areas showed me that moving from solid established grounds into unexplored new directions may be like jumping into cold water but also most exciting and successful. The inspiring creative approaches of my colleague Dr. Matt Cotten in accessing science showed me that joy and fun in good rigorous science itself is much more important than being regarded as successful scientist by your peers.

• 5. Pharmaceutical scientists are faced with the dilemma of having to publish in biomedical or basic science journals. Does it mean cutting edge science will not likely be featured in the Pharmaceutical Research?

  Not, if Pharmaceutical Research makes clear that pharmaceutical sciences are more than just a collection of different disciplines, approaching pharmacy from different angles. If it highlights it as forum for unique cutting edge science that advances the performance of the drug development process, introduces novel drug concepts and improved technology for drug discovery, formulations and accelerated evaluation of clinical safety and efficacy.

• 6. Where is the field of Polymeric Carriers for Nucleic Acid Delivery going? How do the articles in the theme section fill the gap?

  The field has moved into a most interesting age. It started already 45 years ago, developing slowly in the shadow of the more prominent polymer therapeutics field. Clinical developments were limited by moderate efficiency, significant toxicity, and CMC issues in chemistry, manufacturing, quality control of polymers. Step by step solutions for the mentioned problems were developed. About a decade after the first ex vivo gene therapy trial in 1994, recently several in vivo gene therapy trials have been initiated or been completed, demonstrating safety and first encouraging hints for efficacy. The advent of siRNA as possible therapeutic modality provides a further boost for the synthetic polymer field. The articles in the theme section illustrate the different opportunities in the field. For example, a novel noncondensing copolymer is described which augments naked DNA based intramuscular gene transfer. Preclinical pharmacological properties of GMP grade linear PEI in DNA and siRNA polyplexes are interesting as this broadly used transfection agent recently entered several clinical trials. PEG-oligoethylenimine block copolymers with ketal linkages designed to rapidly degrade in endosomes maintain high transfection activity at strongly reduced cytotoxicity. Polyplexes based on a new triblock copolymer have been successfully applied for systemic delivery into pancreatic tumors. Other interesting polymer applications are gene-activated matrices (GAM) for tissue regeneration. An injectable fibrin glue-based GAM based on copolymer protected polyplexes co-lyophilized with fibrinogen are also described in this theme section.

• 7. What are the challenges for Polymeric Carriers for Nucleic Acid Delivery and how can they be overcome?

  Preclinical studies have demonstrated efficacy at acceptable biocompatibility. For broad clinical use, polymeric carriers and their nucleic acid formulations have to remain simple, but should be more effective and more precise. Along these efforts, programmed, i.e. dynamic, bioresponsive polymers which can adapt to the different delivery barriers will enhance the therapeutic window. Improved polymer chemistry including solid-phase, dendron, and dendrimer technology will provide monodisperse polymers with uniform size and topology.

• 8. What is the key to developing successful collaborative relationships?

  Partners have to be complementary in delivering ideas, technologies or materials into the collaboration which otherwise could not be done by the individual groups alone.

• 9. What is your philosophy of educating graduate students?

  I rather act as coach than as supervisor. My philosophy is to nurture their own talent and interest in a high scientific standard of performing and describing their experiments. To raise their critical mind and their creativity, to let them find interesting questions and try to solve them. To let them develop the notion that so-called ‘problems’ might actually be the more interesting part of science where we may learn most, and confidence that many problems can be overcome by careful analysis and subsequent measures.

• 10. What are the challenges facing the pharmaceutical sciences?

  Redefining its identity and unique position in a rapidly changing field of bioscience, integrating rising opportunities such as novel molecular therapeutics, genomics/proteomics or individualized medicines.

• 11. What is the place for collaboration with industry in academia?

  Pharmaceutical industry has to be product-driven, with a strong focus on development and finally marketing better drugs for health care. Academia is research-driven, exploring into many directions without market restrictions. Out of serendipity, academia discovers novel mechanisms, technologies, or therapeutic modalities, which only with the expertise and the budget of pharmaceutical industry can be converted into medicines—this is the place and necessity for collaboration.