Enabling Next Generation Gene Medicines October 3-5, 2018 Cell - PowerPoint PPT Presentation

Enabling Next Generation Gene Medicines October 3-5, 2018 Cell & Gene Meeting on the Mesa La Jolla, California Sarah Haecker Meeks, PhD Vice President, Business Development

Synpromics: the leader in gene control Improving human health by enabling safer, more effective cell and gene medicines through proprietary genomics, bioinformatics and intelligent data driven design.

3 Sy Synthetic promoters – dr driving ng the he next next gener generation n of gene gene medi edicine ne New levels of control, stability and precision Greater efficacy and potency, better safety, better targeting Constitutive, inducible and multi-selective promoters Promoter platforms to improve transcriptional control and product performance Product improvement through expression cassette optimization Fine tune dose, lowered COGS, platform is disease, delivery, and vector agnostic Powered by Proprietary bioinformatics and machine learning engine – industrialized, high throughput data driven design, development and validation Center of Excellence for Gene Regulation Comprehensive Subject Matter Experts – bioinformatics, machine learning, molecular biology, cell biology, virology, vectorology

27 4 ACTIVE Commercial Partnerships Programmes Gene Therapy Company Global CDMO Leading Global Biologics company Company Top 10 Pharmaceutical Gene Therapy Company Company Gene Therapy Company

5 Rationale for Promoter Optimization • Promoters provide true targeted tissue • Promoter Types expression and accurate gene control Constitutive Tissue/Cell Selective • Inducible/Repressible • • Synergistic product improvement when Multi-tissue/cell type selective • coupled with tropism of optimized capsid Autoregulatory • • Promoter and expression cassette can be • Lower dose may provide better safety designed according to disease profile profile and/reduce the amount of vector required, increase manufacturing capacity • Promoters are designed in variable sizes solving capacity issues

6 Enabling the development of new gene medicines Center of Excellence for Gene Regulation Constitutive Regulated Gene Intelligent Design for Autoregulatory, Expression Control Greater Gene Control Environmental Control Pharmacologically responsive Pharmacologically responsive Biologically responsive Oral Control Oral Control Adaptive Control Tissue-selective Inducible Dually regulated Self-regulated Variable strength Repressible Multi-gene control Temporally regulated Multi-tissue control Tissue selective Size to specification Pathway control Physiologically regulated Safety switch

7 In Industrialized Multi-di dimens ensiona nal Bioinf nformatics Databa base IN OUT Bioinformatics Novel Human Genome Data Synthetic Promoters ü Systematic and integrative genomics data analysis ü Includes in silico, in vitro, in vivo generated data ü High-throughput, automated screening methodology ü Rapid in vitro and in vivo expression cassette validation

Applications in Gene Medicine

9 Pr Promote ter Pl Platform rms for r Thera erapeu eutic Pro Product Dev Devel elopmen ent 1. Constitutive tissue selective promoters 2nd generation liver selective promoters • Case Study: Development of a small, strong liver selective promoter • 2. Development of inducible and repressible tissue specific promoters 3. Design and development of multi-tissue/cell selective promoters

Fold change over CBA 0.5 1.5 2.5 0 1 2 2 nd CMV nd ge CBA LP1 gene TBG neration HLP SYNP-LVR 1 SYNP-LVR 2 SYNP-LVR 3 n cons SYNP-LVR 4 SYNP-LVR 5 SYNP-LVR 6 nstitut SYNP-LVR 7 SYNP-LVR 8 utive liver selective pr SYNP-LVR 9 SYNP-LVR 10 SYNP-LVR 11 SYNP-LVR 12 Huh 7 Normalised to CBA SYNP-LVR 13 SYNP-LVR 14 SYNP-LVR 15 SYNP-LVR 16 SYNP-LVR 17 SYNP-LVR 18 SYNP-LVR 19 SYNP-LVR 20 promoters SYNP-LVR 21 SYNP-LVR 22 SYNP-LVR 23 SYNP-LVR 24 SYNP-LVR 25 SYNP-LVR 26 SYNP-LVR 27 SYNP-LVR 28 SYNP-LVR 29 SYNP-LVR 30 SYNP-LVR 31 SYNP-LVR 32 SYNP-LVR 33 SYNP-LVR 34 SYNP-LVR 35 SYNP-LVR 36 SYNP-LVR 37 SYNP-LVR 38 10

11 Case Study: Ca Dev Devel elopmen ent of a small, stro rong liver er sel elec ective e pro romoter er Transfection vs Transduction vs in vivo In total 15 promoter designs were tested Promoter D robustly drove expression more than 40-fold stronger compared to A • • HepaRG, HepG2 and primary hepatocytes Successful transfer of relative gene expression strength to a therapeutically relevant gene • • included Lead promoter has less than 5% off-target expression relative to CMV •

12 Li Liver Selecti ctive Induci cible Promote ters Dru Drug Induced ed, dose e res responsive e ex expres ression - LI LIND Promoters 6 0 N o D ru g 0 .8 4 0 N o D ru g 5 D ru g A 5 0 n M 1 µ M D ru g B R a tio to C M V -IE D ru g B 0 .5 u M R a tio to C M V -IE 0 .6 D ru g A 1 5 0 n M 3 0 4 [E P O ]m IU /m L D ru g B 1 u M D ru g A 2 5 0 n M D ru g B 2 u M 3 0 .4 2 0 D ru g B 3 u M 2 0 .2 1 0 1 0 0 .0 0 0 1 0 3 0 4 0 5 0 6 0 7 S Y N -L IN D -0 1 C M V H e p a to c yte s N o n -L iv e r c e lls S Y N -L IN D LIND – Tissue Selective Relative Activity of LIND Multimers LIND – Dose Responsive Drug A and Drug B = FDA Approved Small Molecules

13 Li Liver Selecti ctive Repressi ssible Promote ters Dru Drug Induced ed Rep epres ressed ed Expres ression – LR LREP Promoters 2 0 0 0 D ru g C 2 0 µ M N o D ru g R L U n o rm a lis e d 1 5 0 0 1 0 0 0 5 0 0 0 0 1 0 2 0 3 0 4 C M V-IE S Y N -L R E P Drug C = FDA Approved Small Molecule

14 Mu Multi-Se Selective Promoters Des Designed ed differen erential activity in multiple e targ rget et tissues es 1. Goal Modular approach to design promoters active in multiple distinct tissues and not active in other tissues and production cell lines Challenges Identify important elements of the CREs • Avoid repression between elements • Compatibility between the CREs and the promoters • 2. Construct Design SYNP 1 Tissue A CRE SYNP 2 Tissue B CRE Tissue A CRE Visel et al. Genomics 2009 SYNP 3 Tissue C CRE Tissue B CRE Tissue A CRE 3. Experimental Design & Validation III. Confirmed CRE I. Confirmed CRE II. Confirmed CRE Activity in Tissue B Activity in Tissue C Activity in Tissue A

15 Company Summary ™ – Revolutionary Promoter design technology powered by proprietary Bioinformatics Design and Develop Specific Expression Cassettes – Efficacy, Control and Safety for next generation gene medicine products Regulate Gene Control – inducible and repressible drug- able dose responsive promoters Intellectual Property – Patent Enabling Ease of Technology Access-simple Licensing Model

Co Contact Us If you would like to know more about Synpromics and gene control technology, please get in touch! info@synpromics.com www.synpromics.com Roslin Innovation Centre Easter Bush Campus Midlothian, EH25 9RG