title: Hierarchical scaffold design for mesenchymal stem cell-based gene therapy of hemophilia B.
abstract: Gene therapy for hemophilia B and other hereditary plasma protein deficiencies showed great promise in pre-clinical and early clinical trials. However, safety concerns about in vivo delivery of viral vectors and poor post-transplant survival of ex vivo modified cells remain key hurdles for clinical translation of gene therapy. We here describe a 3D scaffold system based on porous hydroxyapatite-PLGA composites coated with biomineralized collagen 1. When combined with autologous gene-engineered factor IX (hFIX) positive mesenchymal stem cells (MSCs) and implanted in hemophilic mice, these scaffolds supported long-term engraftment and systemic protein delivery by MSCs in vivo. Optimization of the scaffolds at the macro-, micro- and nanoscales provided efficient cell delivery capacity, MSC self-renewal and osteogenesis respectively, concurrent with sustained delivery of hFIX. In conclusion, the use of gene-enhanced MSC-seeded scaffolds may be of practical use for treatment of hemophilia B and other plasma protein deficiencies.
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Coutu
authors.forename: Jessica
authors.initials: J
authors.lastname: Cuerquis
authors.forename: Rouwayda
authors.initials: R
authors.lastname: El Ayoubi
authors.forename: Kathy-Ann
authors.initials: KA
authors.lastname: Forner
authors.forename: Ranjan
authors.initials: R
authors.lastname: Roy
authors.forename: Moïra
authors.initials: M
authors.lastname: François
authors.forename: May
authors.initials: M
authors.lastname: Griffith
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
authors.forename: Azizeh-Mitra
authors.initials: AM
authors.lastname: Yousefi
authors.forename: Mark D
authors.initials: MD
authors.lastname: Blostein
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
mesh_terms: D000818:Animals; D002130:Calcium Phosphates / Q000494:pharmacology; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002516:Ceramics / Q000494:pharmacology; D005164:Factor IX / Q000235:genetics / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D053758:Nanoparticles / Q000648:ultrastructure; D010316:Particle Size; D016062:Porosity / Q000187:drug effects; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D002130:Calcium Phosphates; D005164:Factor IX; C020243:calcium phosphate