Download The Future of Gene Therapy for the CNS: Evolving Perspectives

Georgetown
UNIVERSITY
Overview of Gene Transfer as an
Evolving Neurotherapeutic Modality
Howard J Federoff, MD, PhD
Georgetown University Medical Center
Gene Therapy: a young therapeutic modality
1974:
NIH Creates the Recombinant DNA Advisory Committee- The RAC
1988:
Dr. Rosenberg proposes first gene marking protocol
for tumor infiltrating lympocytes
1990:
RAC approves protocol to treat SCID
with retrovirus carrying adenosine deamidase
1999:
University of Pennsylvania trial with adenovirus results in
death of Jesse Gelsinger
The Not So O.K. Corral
Gene Therapy: a young therapeutic modality
2003:
First Parkinson’s disease gene therapy trial proposed
New Scientist
2006
New Scientist, 2006
Gene Therapy: a young therapeutic modality
2004-2013:
Ten trials completed in neurological diseases
2012:
First gene therapy product approved- Glybera
Pancreatitis
“Gene Therapies Will
Cure Many a Disease”
January 2013
Types of Gene Therapy
» In vivo
in vivo
 Direct gene transfer into the body or organ
ex vivo
» Ex vivo
 Gene introduction into cells outside the body and modified cells reintroduced
» Somatic cell
Brain
 Gene transferred into differentiated cell types
 Episomal or integrated
» Stem cell
 Gene transferred into multi-potent cell types
 Integrated transgene conveys to daughter cells
» Germline
 Gene transferred into germ cell
 Integrated transgene conveys to differentiated cell types
 Integrated transgene conveys to progeny
Clinically Relevant Vectors
C. Sheridan, Nature Biotechnology 29, 121–128 (2011) doi:10.1038/nbt.1769
Contrasting Therapeutic Modalities I
Small Molecule
»
Pharmacokinetics
Gene Therapy
»
 Define t1/2
 CNS/BBB
»
»
 Permanent or long-lived
 Modified by host factors
 Cell type dependent
Pharmacodynamics
 Target engagement
 Dose titration to endpoint
»
Pharmacodynamics
 Target engagement variable
 Nature of encoded gene
 Can be affected by immune responses
Metabolism/Excretion
 Pharmacogenomics
 Hepatic/renal functions
Pharmacokinetics
»
Metabolism/Excretion
 Highly variable
 Dependent on location of expression
 Nature of encoded gene
Contrasting Therapeutic Modalities II
Gene Therapy
Small Molecule
»
Delivery
»
 Routes established
 Typical widespread bioavailability
 Formulation
»
»
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


Toxicity
 Can be dose related
 Off-target
 Contribution of metabolites
Delivery
»
Toxicity





Regulatory path
 IRB, FDA
»
Most approaches use vectors
Can effectively localize expression
Often invasive requireing devices
Tropism can affect locus of action
Vector related
Gene product related
On- and off-target
Immunological
Few options with persistent vectors
Regulatory path
 IBC, RAC, IRB, FDA
The RAC
•
•
•
•
The Rack
The NIH established the Recombinant DNA Advisory Committee
(RAC) on October 7, 1974 because of public concerns regarding
the safety of manipulating genetic material through the use of
recombinant DNA techniques.
The RAC's membership and responsibilities have evolved.
A critically important forum for open, public deliberation on the
panoply of scientific, ethical, and legal issues raised by
recombinant DNA technology and its basic and clinical research
applications.
Comprised of experts from scientific, medical disciplines and
ethicists and members of patient and other lay communities.
Independent Review of the RAC
» IOM request by NIH Director:
 Oversight and Review of Clinical Gene Transfer Protocols:
Assessing the Role of the RAC
» Recommendations:
 Restrict individual gene transfer protocol reviews to exceptional
cases that meet specified criteria




Could not be done by existing bodies (FDA, IRB, IBC) and
New vector, genetic material, delivery methodology
Protocol relies on preclinical data using model of unknown value
Proposed vector, gene construct or delivery method associated with toxicities
that are not widely known
 Consider integrating oversight for gene transfer and other
applications of emerging technologies
ASENT Program on Gene therapy
» FDA perspective
» Delivery
» Movement disorders
» Neuroimaging
» Placebo effect
» Panel discussion