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