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