9:45 Industrial-Scale Genotyping: Identifying, Validating, and Translating Association Findings
Dietrich Stephan, Ph.D., Director & Senior Investigator, Neurogenomics, Translational Genomics Institute
Dissecting the genetic variants that subtley predispose to common and complex human disease requires careful study design considerations, a robust high-throughput environment, and evolving analysis paradigms. If done correctly, the results can routinely be expected to result in therpeutic targets with an order of magnitude more precision than historical strategies, as well as probabalistic risk assessment tools.
10:15 Networking Coffee Break
10:45 Genome Scan of 310 African-American Families for Genes Linked to Higher Risk of Diabetes and Cardiovascular Disease
Michael Christman, Ph.D., President and Chief Executive Officer, Coriell Institute for Medical Research
Obesity, hypertension, type 2 diabetes and their complications are more common among African Americans than European Americans. Collectively, these diseases explain over 80% of the health disparity between the two populations. The Howard University Family Study was developed as a population-based resource of multi-generational African American pedigrees to study the genetic epidemiology of these diseases. We have used the Affymetrix SNP 6.0 arrays combined with a family-based association analysis to identify common genetic factors influencing heritability of these common diseases in African Americans.
11:15 Copy-Number Variation in Control Population Cohorts
Richard F. Wintle, Ph.D., Assistant Director, Center for Applied Genomics, Hospital for Sick Children
In order to understand the contribution of CNV to both normal human variation and disease susceptibility, it is crucial to understand the range and characteristics of CNV variability in healthy population cohorts. Here, we will describe recent work using high-density arrays from the major vendors to ascertain genome-wide copy number. We also describe the development of a novel algorithm for the determination of genomic copy number from these array platforms, and the application of the Database of Genomic Variants containing normal variation data to disease studies.
11:45 Structural Genomic Variation in the Human Genome: The Impact of Copy Number Variants (CNVs) in Clinical Diagnoses
Charles Lee, Ph.D., FACMG, Director of Cytogenetics, Harvard Cancer Center, Assistant Professor, Harvard Medical School, Associate Faculty Member, MIT Broad Institute, and Department of Pathology, Brigham and Women’s Hospital
Genomic imbalances were traditionally thought to be rare and disease causing. However, over the past three years we have come to appreciate that structural genomic variation are wide-spread and many can be very common among healthy individuals. This has complicated accurate interpretation of data being generated from genome-wide comparative genomic hybridiza-tion (CGH) / genotyping platforms being used for clinical diagnoses. Strategies to determine if a particular CNV is pathogenic or benign will be discussed, in the context of our recent studies that define the fine-scale genomic architecture of hundreds of common CNVs.
12:15 pm Close of Morning Session
12:30 Luncheon Technology Workshops
(Sponsorships Available) or Lunch on Your Own
2:00 Chairperson’s Remarks
Michael
Barry, Ph.D., Professor, Internal Medicine, Mayo
Clinic
2:05 Noninvasive Aerosol Gene Delivery for the Lung Cancer Treatment
Myung-Haing Cho, D.V.M., Ph.D., Professor, Public Health, Seoul National University
The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Revisiting of aerosol gene delivery may provide an alternative for safe and effective treatment for lung cancer. Results obtained our group suggest that aerosol delivery of target genes may be compatible with non-invasive in vivo gene therapy.
2:35 Ex vivo Evaluation of Efficacy and Toxicity of Gene Therapy Vectors Using Organ Cultures of Human Solid Tissues
Amos Panet, Ph.D., Chairman, Virology, Hebrew University-Hadassah Medical School
We have developed a generic technology to evaluate gene therapy vectors and transgenes using organ cultures derived form normal and diseased human tissues such as skin, carcinomas, lung, colon etc. Using this approach we determine the tropism of Adeno, Lenti and herpes viral vectors to solid tissues of human origin. This information was applied to evaluate oncolytic viruses and for the development of the Biological pump technology to supply hormones systemically.
3:05 Targeting and Detargeting Gene Therapy Vectors
Michael Barry, Ph.D., Professor, Internal Medicine, Mayo Clinic
Viral gene therapy vectors and oncolytics hold promise to treat genetic diseases and cancer, but are plagued by a lack of cell specificity in vivo. We have utilized peptide-presenting phage libraries to select cell-binding peptides to supply these viruses with new ligands to target the cells of interest. One fundamental problem with this approach is that translation of ligands from the structural context of a phage library into the differing structural context of a virus can fail due to loss of ligand binding or disruption of viral protein function. Approaches to improve phage
selection and to avoid this context problem will be discussed.
3:35 Technology Spotlight
(Sponsorships Available)
3:50 Networking Refreshment Break
4:15 Facilitated delivery of siRNA to the CNS: A Therapeutic Approach for Stroke
Carol M. Troy, M.D., Ph.D., Associate Professor, Pathology, Columbia University
Research on the mechanisms of neuronal death in ischemia has yielded potential targets for therapeutic intervention. However, development of therapies has been hindered by lack of acces-sibility to the brain and the specificity of action of the therapeutic. We have developed a novel non-transfection based delivery of siRNA and peptides in vitro, which employs a transduction peptide, Penetratin1 (Pen1) to deliver the cargo to neurons with 100% efficiency. Pilot studies show that we can use this approach to deliver siRNA in vivo to the CNS. Studies are in prog-ress to test the efficacy of this approach in a rodent model of stroke.
4:45 AAV Mediated Tissue Specific Gene Expression
Hua Su, Ph.D, Assistant Professor, Medicine, Department to Anesthesia and Perioperative Care, University of California, San Francisco
Untargeted gene expression can result in some unwanted side effects caused by cytotoxicity of viral vectors or excessive transgene expression. Each AAV serotypes has its own receptors and thus infect different tissue with different efficiency. With selected AAV serotype combined with hypoxia response element and cardiac specific promoter, we have achieved targeted gene expression in ischemic myocardium. We have expressed genes in ischemic brain with AAV mediated gene transfer.
5:15 Welcoming Reception in the Exhibit Hall
6:30 Close of Day
Tuesday, June 10
7:00 am – 6:00 pm Registration Open
7:30 am Breakfast Workshop
(Sponsorships Available)
8:15 Chairperson’s Remarks
Eric Kmiec, Ph.D., Professor, Biology,
University of Delaware/OrphageniX
8:20 A New Frontier in Gene Therapy
Eric Kmiec, Ph.D., Professor, Biology, University of Delaware/OrphageniX
Over the past seven years, we have pioneered the technique of gene repair wherein genetic mutations are corrected directly within context of the chromosome. This repair is facilitated by oligonucleotides , non-viral drug-like agents that does not induce an immune reaction or cause toxicity in humans. A number of genetic diseases including sickle cell anemia, spinal muscular atrophy and muscular dystrophy have been successfully treated in cell and animal models. Now, the focus is translating these results into a clinical trial.
8:50 Lasting Effects by Transient Gene Transfer: Epigenetics
Casey Case, Ph.D., Vice President Research, SanBio Inc.
Our cell therapy product is produced by transient transfection of Mesenchymal Stem Cells. The vector used encodes the Notch-1 IntraCellular Domain (NICD) a powerful regulator of devel-opmental cell fate. Transfection with this vector causes the cells to assume neuronal precursor-like properties and to lose the ability to differentiate down alternative paths. This beneficial effect persists long after the gene transfer vector is gone. We are exploring epigenetic mechanisms, such as CpG DNA methylation, to explain this phenomenon. These cells have shown beneficial results in models of stroke, Parkinson’s disease and spinal cord injury.
9:20 Sequence-Specific Modification of Genomic DNA by Oligonucleotides
Dieter Gruenert, Ph.D., Professor, Senior Scientist, Cell Biology, California Pacific Medical Center Research Institute
We have developed a strategy small fragment homologous replacement (SFHR) for modifying specific targets in the genomic DNA using small DNA fragments (SDF). Studies in hematopoie-tic stem cells, lymphoblasts, epithelial cells, and embryonic stem cells have shown SFHR-mediated modification. This approach has potential therapeutic applications as well as in the
development of transgenic animals.
9:50 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Nucleic Acid Delivery and Gene Repair in the Eye
John M. Nickerson, Ph.D., Professor, Department of Ophthalmology, Emory University
Short single stranded oligonucleotides (ODNs) can be delivered into photoreceptor cells of the neural retina in vivo. We used a mouse strain bearing the retinal degeneration (rd1) lesion, a point mutation in a gene encoding the beta-subunit of cGMP phosphodiesterase (beta-PDE). Delivery of therapeutic ODNs to rd1 mouse eyes resulted in genomic DNA conversion from mutant to wild type sequence at a low but observable incidence. Correspondingly, observable beta-PDE immunoreactivity was detected. Rhodopsin immunopositive cells were detectable in the outer layers of the retina, suggesting that ODN-directed gene repair occurred in about 0.2% of cells.
11:15 Selected Brief Poster Presentation
