Brief Project Overview:

1. Innovation Enabled by Flow Cytometry Center Keck Graduate Institute of Applied Life Sciences PI: James D. Sterling Co PIs: Jim Osborne, Angelika Niemz, Ziyad Duron, Elizabeth Orwin NSF Award #IIP- 0917906 3 Year Award Start Date: 1 August 2009 Brief Project Overview: This translational and collaborative PFI project involves industry (Beckman Coulter, Inc. (BCI)), a non-profit organization (National Organization of Rare Disorders (NORD)) and academia (Harvey Mudd College (HMC) and Keck Graduate Institute (KGI)) to educate translational scientists and to discover and commercialize new disease-specific biomarkers. As part of the proposed work, we have established the Center for Biomarker Research (CBR) on the KGI campus and have equipped the facility with analytical instruments, including a flow cytometer. Research in CBR will focus on development and validation of biomarker assays for rare diseases. A database of biomarkers is being created and will provide a means for classifying and stratifying disease populations. The entire database of biomarkers and disease characteristics will be accessible to the academic and corporate communities for data mining. CBR will select diseases for further study from the database that have effective therapies, but are difficult to diagnose due to a lack of specific biomarkers, and work with NORD, patient advocacy groups and the medical community for access to biospecimens. The Center will educate Master of Bioscience students at KGI and undergraduate engineering students at HMC in the development of diagnostic tools for biomarker discovery. The students will learn to operate in a Good Laboratory Practice (GLP) facility that handles human samples, an experience that provides excellent preparation for the industrial laboratory work environment. The protocols for the GLP facility will be adopted from existing BCI standard operating procedures and BCI will assist in their full implementation. Through exposure to this facility, the students will gain valuable hands-on experience in quality assurance, assay validation and regulatory compliance, areas that are not commonly addressed in an academic setting. HMC and KGI will arrange for 3-4 students per year to participate in a 10 week summer undergraduate research program at KGI, engaging in team based research related to the PFI award. Dr. Niemz, Dr. Orwin and Dr. Osborne will collaborate on integrating PFI related topics to existing courses at HMC and KGI. Relevant courses include: Engr164/Biol164-Introduction to Biomedical Engineering; ALS320-Medical Diagnostics; ALS301-Molecular Basis of Disease; ALS408-In Vitro Diagnostics; ALS409-High Throughput Technologies. Key Attributes of our Innovation Ecosystem: • Questioning & Curiosity: • Rare Diseases are defined as those with fewer than 200,000 cases per year in the US • The Orphan Drug Act creates seven year market exclusivity for new therapeutic products for rare diseases • However, diagnosis of many of the known 6000-7000 rare diseases is very difficult • Risk Taking: • Patient risk: we may not find a useful biomarker for particular diseases, resulting in continued poor diagnosis • Commercialization of biomarkers: no guarantee that certain biomarkers will be commercialized due to low prevalence of rare diseases Program Activities: • Openness: • A public domain containing a searchable biomarker database for rare diseases will be available for the academic and industry sectors • KGI will apply for patents on identified biomarkers to facilitate commercialization • KGI is open to collaboration with companies interested in commercial development of identified biomarkers • Collaboration Across Fields: • To address roadblocks in innovation and commercialization, a unique partnership is formed between: • Keck Graduate Institute and Harvey Mudd College (Academic) providing the expertise and space for facilities • National Organization of Rare Disorders (Non-profit) with access to patient advocacy groups • Beckman Coulter, Inc. (Corporate) providing standardized operating procedures and analytical instruments for biomarker analysis • FDA-Center for Rare Disease Therapy Workshop on Orphan Drug Applications Disease description:  Hereditary Inclusion Body Myopathies (HIBM) are a diverse group of muscle wasting disorders that share similar histopathology with sporadic Inclusion Body Myositis and senile plaques seen in Alzheimer's brain disease.  Although histologically similar, various forms of HIBM are genetically and clinically diverse. The autosomal recessive form (IBM2) is the most common.  It usually affects young adults, between the age of 20-35 years, and often leads to severe disability and confinement to a wheelchair in 10-15 years.  Although worldwide it is an “orphan” disease, IBM2 is most prevalent amongst people of Iranian-Jewish heritage due to a common founder mutation (GNE:p.M712T), accounting for a carrier frequency of 1-2 in 20, and an prevalence of 1-2 in 1000 persons.  IBM2 is a recessive genetic disorder, which means it can happen to anyone, even without family history of the disease.  Most of the patients have healthy parents who were carriers of the disease without knowing -- the patients and their families had never heard of IBM2 prior to their devastating diagnosis.  HRG:  HIBM Research Group (HRG) is a California non-profit public benefit corporation, founded by Dr. Daniel Darvish, engaging in medical research on HIBM.   Over the past few years, HRG has established a depository center for maintaining and distributing reagents and resources necessary for research on IBM2. They have formed fruitful collaborations with biomedical investigators at universities and at the National Institutes of Health. The major goals of HRG are: 1) further clarifying the molecular mechanism that leads to IBM2 muscle damage, 2) prevention of muscle damage cause by IBM2, and 3) muscle regeneration. HRG and KGI collaboration:  As in many rare disorders, for IBM2 there is a significant need to develop biomarkers that can be useful in clinical and molecular evaluation of the disease.  Such biomarkers will allow us to monitor progression of the disease and determine the effectiveness therapy early in clinical trials, which may translate to significant cost and time savings.  KGI and HRG have begun a team oriented effort to develop and validate IBM2 specific biomarkers. Top Contributions: Adding flow cytometry and DNA sequencing capabilities in a Good Laboratory Practice facility on the KGI campus Education of the medical community on the molecular basis of disease, which is fundamental to adoption of personalized medicine Development of intellectual property for entrepreneurial activity and licensing opportunities for rare disease diagnostics and therapies Placing Partners in “New Environments” & “Playgrounds”: Goal: to bridge the gap between discovery and commercialization, enabling a crucial discovery to translate into a useful product that will improve the lives of the many people with rare diseases Partners: Top Challenges: Identifying diseases that have effective therapies, but poor diagnostic biomarkers Securing the necessary biospecimens for testing Creating a biomarker database that contains information useful for educational purposes as well as for return on investment in commercial applications . PFI . . National Science Foundation Partnerships For Innovation Grantee’s Meeting April 25-27, 2010 Arlington, VA