forward-looking research: the potential of new genetic technologies
DESCRIPTION
Dr. James Gusella discusses the research cycle of Norrie Disease. (NDA International Conference, 2009)TRANSCRIPT
James F. Gusella, PhD Center for Human Genetic Research -
Massachusetts General Hospital
Forward-looking Research: Forward-looking Research: The Potential of New The Potential of New
Genetic TechnologiesGenetic Technologies
Effective ND TherapiesEffective ND Therapies
This is the ultimate mission of Norrie Disease investigators/clinicians
1) Pharmaceutical: traditional small molecule drugs
2) Biological: proteins, gene manipulation
3) Medical device
Potential types of therapeutic Potential types of therapeutic interventionintervention
Molecular Target
Screenchemicalcompounds
Optimizeselectedcompounds
Preclinicaltesting-modelsystems
Phase 1Clinical Trial
Phase 2Clinical Trial
Phase 3Clinical Trial
FDAapproveddrug
Traditional Pharmaceutical Development Traditional Pharmaceutical Development
Basic Research
Applied Research
Clinical Trial Research
Flexibility,variety of strategies
Therapeutic developmentTherapeutic development
It requires 3 different kinds of research:
Basic/Discovery research
Applied/translational research
Clinical trial research
Why not just guess at a drug?
Why not just guess at a target or test all of them?
Norrie Patientsand Families
Description of disorder
Identification ofNorrie disease gene How do norrin
mutations causedisease symptoms?
Diagnostics, Management and Therapy
Norrie DiseaseNorrie Disease Genetic Genetic
Research Research CycleCycle
Norrin protein
Norrin
How do mutationscause
disease symptoms
Why?To identify a specific molecular targetor pathway against which an effective drug can be developed
How?Basic Research
How to define the effects of the Norrie disease mutation?
• Advances in high throughput biology – permits unbiased mining of large datasets and definition of global pathway changes
• Advances in DNA sequencing are opening up the search for factors that modify disease
• Advances in stem cell technology will permit the study of norrin function in authentic human cells of different types
Genetic models with inbred mice areidentical clones of each other
50 72 80
92 111 150
Manual DNA sequencing:
from theera of Norrie gene discovery
Only a few hundred thousand basesper person per year
Semi-automated DNA sequencing:
Led to sequencing of the entire human genome for ~3 billion dollars
Automated “next-generation DNA sequencing:
Currently can provide full genome sequence for $5,000-$20,000
Expected to drop to less than $1,000 with 1-2 years
Realistic to sequence whole genomes and for other applications to more rapidly identify factors that modify disease – identify targets and pathways for therapeutic intervention that are already validated in humans or human cells
Despite appearances, mice are not people
Stem cells and iPS cell
Pluripotent stem cells can be made from adult skin cells
Advances in applied researchAdvances in applied research• Pharmaceutical companies are beginning to
investigate a pathway-based therapeutic approach
• Human cell models may be more predictive of potential therapeutic benefit than non-human models
• Research advances in the ability to manipulate gene expression: RNA interference, microRNAs, sequence specific targeting
• Research advances in experimental delivery systems for gene-based biologicals
Research requires the cooperation and participation of patients at all stages for:
1) detailed description of disease in all its aspects
2) biological samples for discovery and applied research
3) clinical research into effectiveness of candidate interventions
Empowering the Research PipelineEmpowering the Research Pipeline
Thank you