James F. Gusella, PhD Center for Human Genetic Research - Massachusetts General Hospital Forward-looking Research: The Potential of New Genetic Technologies

Effective ND Therapies This is the ultimate mission of Norrie Disease investigators/clinicians Pharmaceutical: traditional small molecule drugs Biological: proteins, gene manipulation Medical device Potential types of therapeutic intervention

Pharmaceutical: traditional small molecule drugs

Biological: proteins, gene manipulation

Medical device

Molecular Target Screen chemical compounds Optimize selected compounds Preclinical testing- model systems Phase 1 Clinical Trial Phase 2 Clinical Trial Phase 3 Clinical Trial FDA approved drug Traditional Pharmaceutical Development Basic Research Applied Research Clinical Trial Research Flexibility, variety of strategies

Therapeutic 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 Patients and Families Identification of Norrie disease gene How do norrin mutations cause disease symptoms? Diagnostics, Management and Therapy Norrie Disease Genetic Research Cycle Description of disorder

Norrin protein

Norrin

How do mutations cause disease symptoms Why? To identify a specific molecular target or 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

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 are identical clones of each other 50 72 80 92 111 150

Manual DNA sequencing: from the era of Norrie gene discovery Only a few hundred thousand bases per 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 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

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: detailed description of disease in all its aspects biological samples for discovery and applied research clinical research into effectiveness of candidate interventions Empowering the Research Pipeline

Research requires the cooperation and participation of patients at all stages for:

detailed description of disease in all its aspects

biological samples for discovery and applied research

clinical research into effectiveness of candidate interventions

Thank you