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

Improving human health by enabling safer, more effective cell and gene medicines through proprietary genomics, bioinformatics and intelligent data driven design.

Synpromics: the leader in gene control

Sy Synthetic promoters – dr driving ng the he next next gener generation n of gene gene medi edicine ne

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Constitutive, inducible and multi-selective promoters

Promoter platforms to improve transcriptional control and product performance

New levels of control, stability and precision

Greater efficacy and potency, better safety, better targeting

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Proprietary bioinformatics and machine learning engine – industrialized, high throughput data driven design, development and validation

Product improvement through expression cassette optimization

Fine tune dose, lowered COGS, platform is disease, delivery, and vector agnostic

Center of Excellence for Gene Regulation

Comprehensive Subject Matter Experts – bioinformatics, machine learning, molecular biology, cell biology, virology, vectorology

Partnerships

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Global CDMO Company Gene Therapy Company ACTIVE

Commercial Programmes

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Leading Global Biologics company Gene Therapy Company Top 10 Pharmaceutical Company Gene Therapy Company

• Promoters provide true targeted tissue

expression and accurate gene control

• Synergistic product improvement when

coupled with tropism of optimized capsid

• Promoter and expression cassette can be

designed according to disease profile

• Promoters are designed in variable sizes

solving capacity issues

• Promoter Types
• Constitutive Tissue/Cell Selective
• Inducible/Repressible
• Multi-tissue/cell type selective
• Autoregulatory
• Lower dose may provide better safety

profile and/reduce the amount of vector required, increase manufacturing capacity

Rationale for Promoter Optimization

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Constitutive Expression

Tissue-selective Variable strength Multi-tissue control Size to specification

Regulated Gene Control

Pharmacologically responsive Oral Control

Inducible Repressible Tissue selective Safety switch

Intelligent Design for Greater Gene Control

Pharmacologically responsive Oral Control

Dually regulated Multi-gene control Pathway control

Autoregulatory, Environmental Control

Biologically responsive Adaptive Control

Self-regulated Temporally regulated Physiologically regulated

Enabling the development of new gene medicines

Center of Excellence for Gene Regulation

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Bioinformatics

Human Genome Data

Novel Synthetic Promoters

In Industrialized Multi-di dimens ensiona nal Bioinf nformatics Databa base

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IN OUT

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

• 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

Pr Promote ter Pl

Platform rms for r Thera erapeu eutic Pro Product Dev Devel elopmen ent

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2nd

nd ge

gene neration n cons nstitut utive liver selective pr promoters

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0.5 1 1.5 2 2.5 CMV CBA LP1 TBG HLP SYNP-LVR 1 SYNP-LVR 2 SYNP-LVR 3 SYNP-LVR 4 SYNP-LVR 5 SYNP-LVR 6 SYNP-LVR 7 SYNP-LVR 8 SYNP-LVR 9 SYNP-LVR 10 SYNP-LVR 11 SYNP-LVR 12 SYNP-LVR 13 SYNP-LVR 14 SYNP-LVR 15 SYNP-LVR 16 SYNP-LVR 17 SYNP-LVR 18 SYNP-LVR 19 SYNP-LVR 20 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

Fold change over CBA

Huh 7 Normalised to CBA

Ca Case Study:

Dev Devel elopmen ent of a small, stro rong liver er sel elec ective e pro romoter er

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Transfection vs Transduction vs in vivo

• In total 15 promoter designs were tested
• HepaRG, HepG2 and primary hepatocytes

included

• Promoter D robustly drove expression more than 40-fold stronger compared to A
• Successful transfer of relative gene expression strength to a therapeutically relevant gene
• Lead promoter has less than 5% off-target expression relative to CMV

LIND – Dose Responsive LIND – Tissue Selective Relative Activity of LIND Multimers

Li Liver Selecti ctive Induci cible Promote ters

Dru Drug Induced ed, dose e res responsive e ex expres ression - LI LIND Promoters

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Drug A and Drug B = FDA Approved Small Molecules

S Y N -L IN D -0 1 C M V 1 0 2 0 3 0 4 0

[E P O ]m IU /m L D ru g B 1 u M D ru g B 2 u M D ru g B 3 u M N o D ru g D ru g B 0 .5 u M H e p a to c yte s N o n -L iv e r c e lls 0 .0 0 .2 0 .4 0 .6 0 .8 R a tio to C M V -IE D ru g A 5 0 n M D ru g A 1 5 0 n M D ru g A 2 5 0 n M 0 1 0 3 0 4 0 5 0 6 0 7 1 2 3 4 5 6

S Y N -L IN D R a tio to C M V -IE 1 µM D ru g B N o D ru g

Li Liver Selecti ctive Repressi ssible Promote ters

Dru Drug Induced ed Rep epres ressed ed Expres ression – LR LREP Promoters

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Drug C = FDA Approved Small Molecule

0 1 0 2 0 3 0 4 C M V-IE 5 0 0 1 0 0 0 1 5 0 0 2 0 0 0

S Y N -L R E P R L U n o rm a lis e d N o D ru g D ru g C 2 0 µM

Mu Multi-Se Selective Promoters

Des Designed ed differen erential activity in multiple e targ rget et tissues es

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• 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

Tissue C CRE Tissue B CRE Tissue A CRE Tissue B CRE Tissue A CRE Tissue A CRE

SYNP 1 SYNP 2 SYNP 3

• 3. Experimental Design & Validation
• I. Confirmed CRE

Activity in Tissue A

• II. Confirmed CRE

Activity in Tissue B

• III. Confirmed CRE

Activity in Tissue C

• 2. Construct Design

Visel et al. Genomics 2009

Company Summary

15 ™ – Revolutionary Promoter design technology powered

by proprietary Bioinformatics Intellectual Property – Patent Enabling 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 Ease of Technology Access-simple Licensing Model

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

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