Nbia presentation

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Nbia presentation

  1. 1. Suzanne Jackowski, Ph.D. St. Jude Children’s Research Hospital Seventh International Family Conference NBIA Disorders Association April 6, 2013
  2. 2. Topics • Potential therapy for PKAN – Research sponsored by Retrophin Inc. • Efforts toward a PKAN mouse model – Research sponsored by NBIA Disorders Association
  3. 3. PKAN Disease Pantothenate Kinase-Associated Neurodegeneration • Autosomal recessive • Mutations in PANK2 gene coding sequence • Muscle rigidity, weakness, abnormal postures • MRI – iron deposits basal ganglia • Neurodegeneration • Progressive • Survival 11.2 ± 7.8 years • Prevalence 1 in 106 • Onset <10 years old
  4. 4. Hypothesis • Loss of PanK2 activity leads to reduced cellular CoA in neurons • Reduced cellular CoA underlies the loss of neurons and loss of neuromuscular control
  5. 5. TCA Cycle Acetyl-CoA Glucose Amino Acids Glycogen Coenzyme A Plays a Central Role in Metabolism Ketone bodies Fatty Acids ⊕⊕⊕⊕ Pyruvate CoA CoA CoA pantothenate CoA CoA CoA
  6. 6. Coenzyme A Biosynthesis Pantothenate ………. vitamin B5 P-Pantothenate Coenzyme A (CoA) Pantothenate Kinase (PanK)
  7. 7. • 3 Pank genes & 4 PanK proteins • PanK1α, PanK1β, PanK2 & PanK3 • At least 2 Nudt proteins that degrade CoA • Tissue-selective expression • PanK1 dominates liver • PanK2 dominates brain • PanK3 present in brain, not sufficient • Biochemical interaction between PanK proteins and small metabolic molecules Complex Regulatory Network to Maintain CoA Levels
  8. 8. Retrophin Strategy • Prodrugs designed by Retrophin chemist • Prodrugs added to – Bacteria – Cultured mammalian cells – PanK1 knockout mice • Evaluated for toxicity, growth, CoA levels • Proof-of-principle to bypass genetic block
  9. 9. PanK1 Knockout Mouse Model • Genetic deletion of Pank1 gene • Substitute for PKAN mouse model – not yet on the scene • Reduced CoA in liver – not brain • Assess efficacy of prodrug metabolism • Does not address transit across BBB
  10. 10. Aim: To Restore Coenzyme A Biosynthesis Pantothenate ………. vitamin B5 P-Pantothenate Coenzyme A (CoA) PanK2 PantothenatePRE024
  11. 11. Progress Report • Sponsored Research Agreement started July 1, 2012 • Bacterial screen completed – no cytotoxicity • Methodology developed for CoA measurements – Faster, more sensitive • Cultured cell experiments ongoing – Evaluation of prodrug metabolism prior to mice • PanK1 KO mouse experiments initiated & ongoing • Positive results thus far
  12. 12. Plans • To continue testing Retrophin compounds in PanK1 KO mice
  13. 13. Acknowledgements Retrophin Martin Shkreli Andrew Vaino Tom Fernandez Marek Biestek St. Jude Children’s Research Hospital Roberta Leonardi Caroline Pate Matt Frank Lois Richmond Katie Wells

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