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ASENT 2009

ASENT 2009. Biomarkers for Monitoring Treatment with HDAC Inhibitors James Rusche, PhD Repli Gen Corporation. HDAC Inhibitors as a Drug Target. HATs (histone acetyltransferases) are responsible for acetylation HDACs (histone deacetylases) are responsible for deacetylation.

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ASENT 2009

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  1. ASENT 2009 Biomarkers for Monitoring Treatment with HDAC Inhibitors James Rusche, PhD RepliGen Corporation

  2. HDAC Inhibitors as a Drug Target HATs (histone acetyltransferases) are responsible for acetylation HDACs (histone deacetylases) are responsible for deacetylation • There are 11 identified HDAC enzymes which vary in tissue expression, ontogeny, and target proteins for deacetylase activity. • Pan inhibitor (SAHA) approved for treating cancer (Vorinostat). • Many cell culture and animal studies have suggested HDAC inhibition is efficacious in both neurodegenerative and neuropsychiatric diseases.

  3. Trinucleotide Expansion Diseases All have transcription dysregulation but Friedreich’s Ataxia is an intronic insert with repeat length correlated to level of RNA and protein Taken from: www.brain.riken.jp

  4. HDAC Inhibitor Can Increase Frataxin Expression ChIP at frataxin gene indicates hypoacetylation Patient PBMC incubated with HDACi for 48 hr Relative Quantity RGFP109 Dose Response (M) Nat Gen (2006)v2,p551

  5. Drug Effects on Gene Expression by Microarray 10 FRDA 10 Carrier 10 Control Ficoll Leukocyte Isolation DMSO Control HDACi 48h Illumina BeadChip Human Arrays Data Analysis

  6. Gene Expression Changes Across Subject Types • Drug induced expression changes generally common across subject type • Large portion of genes with unique patient expression pattern are reversed by HDACi treatment FRDA Carrier FRDA106 Control106 Carrier106

  7. QPCR Characterization of Drug Signature Genes Pilot: Use 9 subjects with 23 genes to identify subset with consistent response to drug 15 FRDA 15 Carrier 15 Control Ficoll Leukocyte Isolation DMSO Control HDACi 48h RT-QPCR- TAQMAN Data Analysis

  8. ***(<.0019) Fxn Induction Significantly Higher in FRDA Cells Frataxin is a Disease Response Biomarker A. FXN Transcript Level in Patients B. FXN Induction in Response to 10 M RGFA8 NS NS Relative Quantity Relative Quantity ***(<.0001)

  9. FRDA Carrier Control FXN STX1A CRIP2 FXYD1 PTRF Drug Effect Uniform Across All Subjects Log2 Fold Change Drug Effect Genes

  10. : avg microarray LFC for gene Comparison of Microarray and RT-QPCR Log2 Fold Change Drug Effect Genes

  11. Biomarker for Monitoring HDACi Activity • HDAC inhibitors can show gene expression changes unique to a genotype or are common across subject groups • RT-QPCR can be used to monitor “drug signature” genes in diverse subject groups • Gene expression measures may prove useful to characterize pharmacodynamic effects of HDAC inhibitors in early trials of Neurodegenerative conditions

  12. Scripps Research Institute R. Brady D. Herman L. Soragni J. Gottesfeld UCLA G. Coppola D. Geschwind CHoP J. Farmer D. Lynch Erasme Hôpital Brussels M. Rai M. Pandolfo Repligen H. Plasterer A. Cooper S. Sharma M. Belmonte S. Sethumadhavan J. Rusche FARA GoFAR MDA Collaborations

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