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Combination Gene Therapy, Bone Marrow Transplantation and Substrate Reduction Therapy for Globoid Cell Leukodystrophy (Krabbe Disease)

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  • 1. Combination Gene Therapy, Bone Marrow Transplantation and Substrate Reduction Therapy for Globoid Cell Leukodystrophy (Krabbe Disease) Mark S. Sands, Ph.D. Washington University School of Medicine
  • 2. Globoid-Cell Leukodystrophy - CNS and PNS involvement - Galactocerebrosidase deficiency (lysosomal enzyme) - Demyelinating disease - Rapid psychomotor deterioration - Seizures (Krabbe Disease) - Premature death (~2-5 yr) -Current treatment strategy - bone marrow transplantation - cord blood transplantation - partially effective
  • 3. Murine Model of Krabbe Disease (Twitcher Mouse) • Galactocerebrosidase-deficient • De/Dysmyelinating disease • Central and peripheral neuropathy • Infiltrating immune cells • Rapid progression (life span ~40d) • Severe tremor • Hind limb ataxia • BMT partially effective – Day 10 – 80d life span – Day 1 – 45d life span WT Twi
  • 4. CNS-Directed AAV-Mediated Gene Therapy & Bone Marrow Transplantation
  • 5. Single Therapies- Too Narrow a Focus? • GLD is a complex disease involving multiple systems and mechanisms Primary Genetic Defect Inflammation Death and Destruction Bone Marrow Transplant Gene Therapy Accumulation of substrates ? ?
  • 6. Combination Therapy (AAV2/5 and BMT) Genotype PND2 PND3 PND4 i.c. and i.t. injection of GALC-AAV2-5 400rads radiation i.v. injection of GFP+ BM cells
  • 7. GALC Activity Reddy AS, et al., (2011) J. Neurosci 31:9945
  • 8. Psychosine
  • 9. Behavior, etc
  • 10. Life Span (≈130 d) (≈70 d)
  • 11. Mechanism of Synergy
  • 12. Neuroinflammation
  • 13. Astrocytosis (GFAP)
  • 14. Activated microglia/macrophages (CD68)
  • 15. Life Span (≈130 d) (≈70 d)
  • 16. CNS-Directed AAV-Mediated Gene Therapy & Bone Marrow Transplantation & Substrate Reduction Therapy
  • 17. Triple Combination (Rationale) Primary Genetic Defect Inflammation Death and Destruction Bone Marrow Transplant Gene Therapy Accumulation of substrates Substrate Reduction Therapy L-cycloserine Biswas & Levine (2002) Pediatric Research 51:40.
  • 18. AAV2/5, BMT and L-cycloserine experimental design Genotype PND2 PND3 PND4 i.c. and i.t. injection of GALC-AAV2-5 400rads radiation i.v. injection of GFP+ BM cells 3X weekly injections of L-cycloserine 50mg/kg
  • 19. Conclusions 1) Single treatments are minimally to marginally effective for Krabbe disease 2) CNS-directed gene therapy and BMT synergize to greatly increase efficacy 3) BMT provides immunomodulatory effects 4) Further synergy is observed when substrate reduction therapy is added to gene therapy and BMT. Question? 1) Can further synergistic improvements be achieved by treating additional therapeutic targets?
  • 20. Acknowledgements Sands Lab: • Shannon Macauley • Marie Roberts • Josh Woloszynek • Adarsh Reddy • Kevin O’Dell • Sarah Hohm • Elizabeth Qin • Jacqui Hawkins • Tom Daly • Darshong Lin • Anthony Frisella Support • NIH - NS43205 & HD55461 • NRSA Fellowship F31 NS056718 • BDSRA Postdoctoral Fellowship • Hunter’s Hope • Legacy of Angels Foundation • Tay-Sachs and Allied Diseases King’s College - London • Catherine Kielar • Andrew Wong • Jonathon Cooper Washington University: • Mike Wong (Seizure Monitoring) • Mingjie Li (Viral Vector Core) • Jin-Moo Lee (GFAP, Vim mice) • Ernie Gonzales (Animal surgery Core) UI Chicago • Ernesto Bongarzone