Suzanne Jackowski, Ph.D.St. Jude Children’s Research Hospital
Seventh International Family Conference
NBIA Disorders AssociationApril 6, 2013
Topics
• Potential therapy for PKAN– Research sponsored by Retrophin Inc.
• Efforts toward a PKAN mouse model– Research sponsored by NBIA Disorders
Association
PKAN DiseasePantothenate Kinase-AssociatedNeurodegeneration
• 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
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
TCACycle
Acetyl-CoA
Glucose
Amino Acids
Glycogen
Coenzyme A Plays a Central Role in Metabolism
Ketone bodies
Fatty Acids
⊕⊕⊕⊕
�
Pyruvate
CoA
CoA
CoA
pantothenate
CoACoA
CoA
Coenzyme A Biosynthesis
Pantothenate ………. vitamin B5
P-Pantothenate
Coenzyme A(CoA)
Pantothenate Kinase(PanK)
• 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 Networkto Maintain CoA Levels
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
PanK1 KnockoutMouse 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
Aim: To Restore Coenzyme A Biosynthesis
Pantothenate ………. vitamin B5
P-Pantothenate
Coenzyme A(CoA)
PanK2
PantothenatePRE024
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
Plans
• To continue testing Retrophincompounds in PanK1 KO mice
Acknowledgements
RetrophinMartin ShkreliAndrew VainoTom FernandezMarek Biestek
St. Jude Children’s Research HospitalRoberta LeonardiCaroline PateMatt FrankLois RichmondKatie Wells