Abstracts

Finding cure for diseases is one of the oldest scientific and medical endeavors. Folk medicine has evolved over the centuries into our biopharmaceutical industry. Compared with other business sectors, the pharmaceutical industry is still by far one of the most innovative and continues to provide the greatest impact to the wealth and health of humankind. The improved general well being of people and the fact that lifespan of the population in many countries has been extended by decades could not have happened without the discovery of new medicine by the pharmaceutical industry. With the continuing advancement in science, e.g., in genomics, proteomics, and bioinformatics, the industry is now entering into a most exciting era. Not only are new therapeutics being continually developed and made available to patients, more sophisticated technologies are also now available to allow for the identification of targets and this has led to new ways of treating both new and old diseases. The changing environment has also plagued the industry where innovation has to compete with patent life and generics, where pricing and reimbursement become the primary driver for making healthcare decisions, where increasing costs in R&D have made it prohibitive to develop drugs with a less than attractive market size even though the target may be a totally unmet medical need, and where importation of drugs has become a political debate. More recently, focus has shifted to the need for even safer drugs leading to the need for more non-clinical and clinical studies, more patients in the clinical drug development programs, and more stringent post marketing surveillance. The presentation will attempt to provide a philosophical view of these changes in our industry. We can take a doom and gloom stance and allow our industry to perish or we can stand up and be recognized to defend and promote our industry ….. how?

Through the emergence of diabetes and obesity as modern day epidemics, the gastrointestinal tract has become the site of increasing interest for its role in assimilating fuel at the time of feeding and the secretion of key hormones involved in fuel homeostasis and body weight control. From the pancreas, the long-standing acknowledgement that insulin is the key anabolic hormone is now complemented by the understanding of companion islet hormones, glucagon and amylin. Glucagon exhibits anti-insulin-like action and likely plays a role in dysregulated glucose homeostasis in diabetes, and amylin, a partner hormone to insulin, plays a role in glucose influx a the time of feeding and body weight control. From the gut, the secretion of two key hormones, GIP and GLP-1, which collectively are responsible for the so-called incretin effect: the signal that augments the beta-cell response to ingested calories. The latter, GLP-1, is also thought to play a role in beta-cell health and body weight control. Through this collective understanding, we have gained new insights into the pathophysiology of the overweight patient with diabetes and are developing potential new therapeutics through the replacement of deficient hormones or by harnessing the incretin effects.

An intriguing, novel phenomenon with possible therapeutic dividends has begun to emerge from our observations of the behavior of neural stem cells (NSCs) in various mouse models of CNS injury & degeneration. During phases of active neurodegeneration, factors seem to be transiently elaborated to which NSCs may respond by migrating (even long distances) to degenerating regions & differentiating specifically towards replacement of dying neural cells. In other words, NSCs may “attempt” to emulate in the brain what hematopoietic stem cells do in the periphery: repopulate & reconstitute ablated regions. These “repair mechanism” may actually reflect the re-expression of basic developmental principles (particularly during particular temporal “windows” following injury) that may be harnessed for therapeutic ends. In addition, NSCs may serve as vehicles for gene delivery and appear capable of simultaneous neural cell replacement & gene therapy (e.g., with factors that might enhance neuronal differentiation, neurite outgrowth, proper connectivity, and/or neuroprotection). Intriguingly, many of these factors are produced spontaneously by the stem cells based on their state of differentiation and do not require ex vivo genetic engineering (though that technique can be used to enhance the expression of certain molecules). When combined with certain synthetic biomaterials, NSCs may be even more effective in “engineering” the damaged CNS towards reconstitution.

An intricate meshwork of many highly-arborized neurites of both host- and donor-derived neurons emerges, and some anatomical connections appear to be reconstituted. The NSCs nestled within damaged parenchyma, altered the trajectory and complexity of host cortical neurites promoting their entrance into the lesion. In a reciprocal manner, tract tracing demonstrated donor-derived neurons extending processes into host parenchyma as far as the opposite hemisphere. Of interest is the degree to which these neurons are capable of seemingly directed, target-appropriate neurite outgrowth without specific external instructive guidance cues, induction, or genetic manipulation of host brain or donor cells. NSCs appear to unveil and/or augment a constitutive reparative response by facilitating a series of reciprocal interactions between NSCs and host CNS tissue (both injured and intact) including promoting neuronal differentiation, enhancing the ingrowth/outgrowth of neural processes, fostering the reformation of cortical tissue, and promoting connectivity following brain injury. Monocyte infiltration and astroglial scarring are also reduced, perhaps facilitating reconstitution. Interestingly, it is to areas of inflammation that NSCs are most drawn.

Background: Human xenograft tumor models are widely used for efficacy evaluation of potential cancer targets, by assessing the anti-tumor effects of specific gene-inactivation agents, such as siRNA. Because of inefficient in vivo delivery, siRNA is usually stably introduced into tumor cells prior to transplantation. However, oncogene silencing results in reduced cell growth/survival in vitro and/or failure to establish tumors in vivo, thus hindering tumor response-based efficacy evaluation that is more relevant from a clinical standpoint. We therefore explored a new tumor response model based on regulated RNAi. Methods: A unique inducible RNAi vector was generated to express shRNA against a target only after induction with doxycylcine. Using this vector, we created a novel xenograft tumor model, in which tumors are established under non-induced conditions, followed by induced target inactivation upon the oral dosing of inducer. Three genes were evaluated, a known oncogene (mTOR), and two novel cancer targets (HE7 and HE26), by assessing the tumor response to their silencing.

Results: We demonstrate for the first time a significant response of staged tumor regression to the gene silencing. For early staged tumors, inactivation of either target caused dramatic tumor regression (100% regresses and 50% becomes tumor-free for both mTOR and HE7, and 100% for HE26). Advanced staged tumors also demonstrated significant responses (100% regression for mTOR, and 75% for HE7, 85% HE26).

Conclusions: Our results support the utility of this new inducible xenograft tumor model for efficacy evaluation of cancer targets; and our data also provide robust in vivo efficacy validations of HE7 and HE26 as novel cancer therapeutic targets.

Myocardial infarction is an ischemia/reperfusion disease in which coronary vessel occlusion induces an initial wave of tissue damage followed by a second wave upon vessel re-opening. Numerous studies have addressed the early ischemic phases of MI development. Unfortunately, patients are inaccessible during much of this period, and it has therefore remained an elusive goal to identify potential therapies that offer cardioprotection post-reperfusion. We have addressed this challenge by targeting signaling pathways involved in late-phase I/R injury. For example, several receptor classes that signal through phosphoinositide 3-kinase induce pathologies (such as vascular edema, leukocyte activation and platelet aggregation) that drive an inflammatory-based myocardial damage. Our lead compound, TG100-115, represents a potent PI3K inhibitor with excellent anti-inflammatory activities, and which limits infarct development when administered in animal models of MI even well after reperfusion. Based in part on these data, TG100-115 has been advanced into clinical trials for reduction of infarct size in acute myocardial infarction.

Pyrimidinone based AMG 476 has been shown to be able to inhibit the release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) from human whole blood. It is a potent p38 MAP kinase inhibitor IC50 = 3 nM with excellent selectivity, no p450 inhibition, good oral bioavalability in rat and dog, excellent aqueous solubility, and demonstration of an ED50 = 0.4 mg/kg for a rat collagen induced arthritis model in vivo.

In previous symposiums, the programs had addressed many topics and issues related to new drug screening and discovery. However, most discussions and presentations, if not all, were mainly focused on preclinical phase of new drug development. In fact, the clinical trial for a new drug plays more critical role for final FDA approval and marketing, and pharmaceutical companies often spend much more money for the clinical phase than that for the preclinical phase. This presentation will address following issues: 1) definition of different phase of clinical trial and FDA procedure and regulation for IND; 2) how to set up and manage a clinical trial; 3) investigator qualification and GCP guideline for clinical trial; and 4) business potentials of organizing clinical trials

Partnering with the university offers a cost-effective way of building the technological foundation of a new company or of bolstering an existing company’s internal R & D programs. This presentation will discuss what UCSD can offer to companies as a component of their business strategies. It will provide an overview of ways for companies to partner with the university, including in-licensing university innovations, sponsoring or collaborating on research projects and grant teaming opportunities.

Developing partnerships can be beneficial for "jumpstarting" your business or accelerating expected growth. Picking the right companies can mean the difference between success and failure. Learn how to make the right choices and what business elements are essential for long term relationships from Beverly Cormier, an executive with more than 18 years of experience in both research and clinical partnerships.

In drug development, speed is critically important for competitive advantage. Every day's delay in the development of a blockbuster medicine can literally cost millions of dollars. This presentation outlines a six-step plan to help drug developers win the race.

1. Pick the right race to run
2. Plan for success
3. Select the fittest runner
4. Remove obstacles
5. Start early
6. Adopt winning approaches

The R&D outsourcing market is predicted to grow from $9.3 billion in 2001 to $36.0 billion by 2010, representing an average annual growth rate of 16.3% (compared with an average growth in global R&D expenditure of 9.6% during the same period). For many pharmaceutical and biotechnology companies, strong science and innovation in R&D is the core of the competitive differentiation. To outsource a large portion of activities in an area so critical to their business will require considerable faith that outsourcing vendors can generate this competitive advantage for them. How to build a strong partnership is the key to successful R&D outsourcing.

CapitalBio and its affiliated National Engineering Research Center for Beijing Biochip Technology are housed in a 260,000 square feet facility in the Zhongguancun Life Science Park, the home to a number of life science and innovative pharmaceutical companies in Beijing, China. CapitalBio and the center have attracted many world-class scientists and specialists from the U.S. and Europe, among their more than 300 staff. With three subsidiary and portfolio companies, AVIVA Biosciences in San Diego, California, Chipscreen Biosciences in Shenzhen and Wandong Medical Equipment Co. in Beijing, CapitalBio has developed cutting-edge and integrated platform technologies for Biochips, Bioautomation and Biomaterials. Its products such as LuxScanTM 10K Confocal Scanners, SmartArrayerTM, HLA Typing System and other gene and protein chip products are on the markets in Asia, the U.S and Europe. CapitalBio is poised to become an industrial leader in a wide range of fields from life science research to bio-safety tests, clinical diagnostics and drug discovery.

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