1. Scientific Drivers Technology in Development Issues Viral vectors
rAAV 2, 4, 5
Physical stability, small size; Transduction efficiency;
Chromosome integration
Helper virus contamination, immune response
eliminated
Long-term transgene expression
Linear dose-response
Initial Phase 1 study results
Issues
Safety
Efficiency
Manufacturing

2. Porous biomaterial scaffolds - natural polymers, e.g. collagen
Scientific Drivers
Porous biomaterial scaffolds - natural polymers, e.g. collagen
Technology in Development
Recombinant collagen
Issues
Safety
Efficiency
Manufacturing
Formulation

3. Scientific Drivers 2 6 12 18 Technology in Development Multiple genes
Potential synergies between DNA vectors and porous biomaterial scaffolds
Technology in Development
Multiple genes
Printing
Scaffold composites
MEMS
Weeks
in-life 2 6 12 18
100.0-mg pMat-1

4. Key Challenge
Safety
Interaction between gene-based therapy and tissue at delivery site
Vector persistence and bioavailability
Interaction between gene-based therapy and immune system
Local and systemic PK/PD of vector-encoded protein

5. Regulated transgene expression
Key Challenge
Regulated transgene expression
Low baseline expression
High induction ratio
Positive control by small molecule drug

6. DNA vector and porous biomaterial scaffold
Control Parameters
DNA vector and porous biomaterial scaffold
Variation associated with site and extent of tissue injury
Rate constants for cell proliferation-migration within biomaterial scaffold
Gene transfer efficiency
Rate constants for therapeutic protein production
Pharmacokinetics and pharmacodynamics of vector-encoded protein
Safety factors that influence gene transfer efficiency
Transgene silencing