1. Suzanne Jackowski, Ph.D.
St. Jude Children’s Research Hospital
Seventh International Family
Conference
NBIA Disorders Association
April 6, 2013

2. Topics
• Potential therapy for PKAN
– Research sponsored by Retrophin Inc.
• Efforts toward a PKAN mouse model
– Research sponsored by NBIA Disorders
Association

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. 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. 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. Coenzyme A Biosynthesis
Pantothenate ………. vitamin B5
P-Pantothenate
Coenzyme A
(CoA)
Pantothenate Kinase
(PanK)

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. 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. 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. Aim: To Restore
Coenzyme A Biosynthesis
Pantothenate ………. vitamin B5
P-Pantothenate
Coenzyme A
(CoA)
PanK2
PantothenatePRE024

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. Plans
• To continue testing Retrophin
compounds in PanK1 KO mice

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