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Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health
Marc Muskavitch
Sr. Director, Epigenetics
September 10, 2014
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2.
Epigenetic Therapeutics
Epigenetics (“over” or “upon” - genetics) is the study of (heritable) changes in gene function that depend on mechanisms other than changes in DNA sequence
Consensus 2013
“an epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence”
Berger et al., 2008
“the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms”
Holliday, 1990
‘‘the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being”
Waddington, 1942
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3.
Epigenetic Therapeutics
RNA BiologyLong Noncoding RNAs
Micro RNAsRNA Editing
Chromatin BiologyHistone Writers/Erasers
Histone Readers/RemodelersDNA Methylation
Wahlestedt Nat Rev Drug Disc 2013Arrowsmith et al Nat Rev Drug Disc 2012
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4.
Epigenetic Therapeutics
Epigenetics and disease• Mutations in genes encoding epigenetic modifiers (e.g., HDAC, HAT, DNMT, MECP) and ncRNAs are associated with human disease• Antagonists of histone deacetylases are moving into the clinic• Anti-sense RNA-based therapies are moving into the clinic
Ensemble therapeutics• Epigenetic therapeutics can be considered “ensemble
therapeutics” because drugs directed against an epigenetic function will affect the expression/function of multiple targets
• Chromatin writers/erasers/readers interact with multiple sites• Antisense RNAs target multiple mRNAs and/or ncRNAs
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5.
Epigenetic Therapeutics
Histones and DNA are modified by a variety of enzymes
• HAT: histone acetyl transferase• HDAC: histone
deacetylase• HMT (KMT): histone
methyltransferase• HDM (KDM): histone demethylase• DNMT: DNA
methyltransferase
Peterson and Laniel Curr Biol 2004Yandell The Scientist 2014
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6.
Epigenetic Therapeutics
Open (active/transcribed) and closed (inactive/ nontranscribed) configurations of chromatin
Klug et al 2011
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7.
Epigenetic Therapeutics
Klug et al 2011
miRNA regulation and RNA interference lead to targeted RNA degradation
microRNA (miRNA) precursors are transcribed in the nucleus, then processed into mature miRNAs by Dicer
miRNAs bind to the RNA-induced silencing complex (RISC) and catalyze degradation of messenger RNAs and noncoding RNAs
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8.
Epigenetic Therapeutics
Klug et al 2011
Dicer cleaves double-strand RNA (including double-strand RNA viruses) into 21 nucleotide fragments
These 21 nt silencing RNAs (siRNAs) bind to the multicomponent RISC
RISC targets for degradationmessenger RNAs and noncoding RNAs, complementary to the bound siRNA
Anti-viral defense system
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Diseases associated with mutations in epigenetic modifiers
Gos Acta Neurobiol Exp 2013
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10.
Epigenetic Therapeutics
Chromatin BiologyHistone Writers/Erasers
Histone Readers/RemodelersDNA Methylation
Arrowsmith et al Nat Rev Drug Disc 2012
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11.Arrowsmith et al Nat Rev Drug Disc 2012
HDAC and sirtuin inhibitors in clinical development
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12.
Long noncoding RNAs implicated in human disease
Wahlestedt Nat Rev Drug Disc 2013
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13.
Epigenetic Therapeutics
RNA BiologyLong Noncoding RNAs
Micro RNAsRNA Editing
Wahlestedt Nat Rev Drug Disc 2013
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14.
Anti-sense RNA therapeutic pipeline at Isis Pharmaceuticals
http://www.isispharm.com/Pipeline/index.htm
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15.
Epigenetic Therapeutics
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16.
Epigenetic Therapeutics
Modalities for epigenetic therapies
Small molecules: antagonists and agonists of epigenetic modifiers(oral, subcutaneous, intravenous)
Biologics (antibodies, factors): inhibitors or substitutes for epigenetic modifiers (oral, subcutaneous, intravenous)
Antisense oligonucleotides (ASOs): reduction of RNA levels by RNA interference (subcutaneous, intravenous, intrathecal)
Cell and gene therapy: genome editing (ZFN, TALEN, CRISPR), antisense, noncoding or coding RNA delivery (viral vectors)
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17.
Epigenetic Therapeutics
Company Target Indication Molecule/ ID Status
Acetylon Pharmaceuticals HDAC6 Lymphoma, Multiple Myeloma ACY-1215 Phase I/II
Constellation EZH2BET
LymphomaLymphoma SM CPI-0610
PreclinicalPhase I
Epizyme DOT1LEZH2
Leukemia NHL
EPZ-5676EPZ-6438
Phase I/IIPhase I/II BCL
GlaxoSmithKline LSD1BET
SCLC, LeukemiaCancer
GSK2879552GSK525762
Phase IPhase I
Eisai (with Epizyme) EZH2 BCL E7438 Phase I/II
Salarius LSD1 Ewing’s Sarcoma SP-2528 Preclinical
Zenith Pharmaceuticals BET Hematologic Cancers ZEN-3365 Preclinical
Drug development pipeline (in part)
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Epigenetic Therapeutics
HDACi approved by FDA for clinical use• Vorinostat Cutaneous T cell lymphoma (Merck)• Romedepsin Cutaneous T cell lymphoma (Gloucester Pharmaceuticals)• Belinostat Peripheral T cell lymphoma (Spectrum Pharmaceuticals) HDACi side effects/liabilities• Fatigue• Nausea/diarrhea• Thrombocytopenia• Cardiotoxicity (prolonged QT interval, hERG effects)
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19.
HDAC6-selective inhibitor in clinical trials• Ricolinostat (Acetylon Pharmaceuticals)
Indications• Multiple myeloma With bortezomib or lenalidomide, and dexamethasone• Relapsed-and-refractory multiple myeloma With pomalidomide and dexamethasone• Relapsed/refractory lymphoid malignancies
Epigenetic Therapeutics
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Epigenetic Therapeutics
DNMTi approved by FDA for clinical use• Azacitidine (Pharmion Corporation)• Decitabine (InnoPharma) Myelodysplastic syndrome DNMTi side effects/liabilities• Neutropenia• Thrombocytopenia• Anemia• Pneumonia• Fatigue
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Epigenetic Therapeutics
ASOs approved by FDA for clinical use• Mipomersen (ApoB) (Isis Pharmaceuticals/Genzyme) Familial hypercholesterolemia• Fomivirsen (Isis Pharmaceuticals/Ciba Vision Corporation) Cytomegalovirus retinitis
ASO side effects/liabilities• Prolonged activated partial thromboplastin time (aPTT)• Activation of alternative complement pathway • Pro-inflammatory reactions• Elevation of hepatic enzymes (ALT, AST)
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22.
Epigenetic Therapeutics
Common drugs with known/possible epigenetic impacts
Csoka and Szyf Med Hypoth 2009
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23.
Epigenetic Therapeutics
Epigenetic drugs and pregnancy/breastfeeding• Should epigenetic therapeutics be avoided during
conception, pregnancy and breastfeeding?
• For vorinostat, romedepsin, belinostat:US FDA Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
Csoka and Szyf Med Hypoth 2009
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24.
Epigenetic Therapeutics
RNA BiologyLong Noncoding RNAs
Micro RNAsRNA Editing
Chromatin BiologyHistone Writers/Erasers
Histone Readers/RemodelersDNA Methylation
Wahlestedt Nat Rev Drug Disc 2013Arrowsmith et al Nat Rev Drug Disc 2012
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25.
Epigenetic Therapeutics
Epigenetics and disease• Mutations in genes encoding epigenetic modifiers (e.g., HDAC, HAT, DNMT, MECP) and ncRNAs are associated with human disease• Antagonists of histone deacetylases are moving into the clinic• Anti-sense RNA-based therapies are moving into the clinic
Ensemble therapeutics• Epigenetic therapeutics can be considered “ensemble
therapeutics” because drugs directed against an epigenetic function will affect the expression/function of multiple targets
• Chromatin writers/erasers/readers interact with multiple sites• Antisense RNAs target multiple mRNAs and/or ncRNAs
![Page 26: Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health](https://reader036.vdocuments.us/reader036/viewer/2022062518/56813f7a550346895daa686f/html5/thumbnails/26.jpg)
Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health
Marc Muskavitch
Sr. Director, Epigenetics
September 10, 2014