Slide 1: Assessment of an AAV-Based Gene Therapy (GJB2-GT) for DFNB1 in Cynomolgus Monkeys
Assessment of an Adeno Associated Vector-Based Gene Therapy (GJB2-GT) for the Non-Syndromic Deafness 1 (DFNB1) in Cynomolgus Monkeys Laurent Désiré, PhD ARO 2024 1
Slide 2: Disclaimer
DISCLAIMER • This document has been prepared by Sensorion (the “Company”) and is provided for • This document contains certain forward-looking statements. These statements are not information purposes only. This document does not purport to contain comprehensive guarantees of the Company’s future pe
Slide 3: Sensorion's Gene Therapy Programs Target Rare Auditory Diseases
Sensorion’s Gene Therapy Programs Target Rare Auditory Diseases FIRST PROGRAMS RESULTING FROM THE INSTITUT PASTEUR COLLABORATION OTOFERLIN DEFICIENCY GJB2-RELATED HEARING LOSS • Patients with mutations in OTOF suffer from severe to profound Three forms of hearing loss are associated with GJB2 gene m
Slide 4: Connexin 26: a Gap-junction Protein Encoded by GJB2 Gene
Connexin 26: a Gap-junction Protein Encoded by GJB2 Gene and Responsible for Tissue Homeostasis Mutations in the Gene Lead to Deafness Background Gjb2 expression in the cochlea • GJB2 is the gene encoding for the Connexin 26 protein; one of 20 known connexins • Cx26 and Cx30 proteins are the dominat
Slide 5: Goals of GJB2 Gene Therapy
Goals of GJB2 Gene Therapy Cx26 is involved in the K+ homeostasis • GJB2 mutations induce loss of Cx26, disrupting K+ homeostasis and endocochlear potential • The aim of GJB2-GT is to o Restore gap junctions in the cochlea o Restore hair cell function and prevent their degeneration o Restore hearing
Slide 6: GT-GJB2 Initial Criteria for Development
GT-GJB2 Initial Criteria for Development CRITERIA LEAD CANDIDATE Natural and synthetic AAV capsid libraries screening for broad coverage of target cells Expression cassette design for high-level of target cells transduction Avoiding off-target expression (i.e. hair cells) : promoter and regulatory s
Slide 7: In Vitro Evaluation
In Vitro Evaluation • Cx26 is addressed at the plasma membrane • Addition of a Flag tag does not impact localization • Next step is demonstration of functional gap junctions hGJB2 hGJB2-Flag Copyright by Sensorion - 2024 - All Rights Reserved 7
Slide 8: Our Lead Candidate Demonstrates Broad Coverage of Relevant Cochlear Cells While Detargeting Hair Cells
Our Lead Candidate Demonstrates Broad Coverage of Relevant Cochlear Cells While Detargeting Hair Cells WT mouse Non- human primate Proprietary injection device developed AAV GFP no to inject a defined RegSeq volume at a controled flow rate Cleared for clinical use AAV GFP + RegSeq *****:p <0.0001 IH
Slide 9: Evidence for Long-term Local Tolerability in Mice
Evidence for Long-term Local Tolerability in Mice Example of ectopic Cx26 expression in HC ABR thresholds in WT mice following GT-GJB2 and cell loss in WT mice injection 120 100 D15 GT-GJB2 FLAG 80 ABR Threshold GT-GJB2 (dB SPL) 60 40 FVB mice - not injected 20 FVB mice - vehicle 8 16 24 32 120 Freq
Slide 10: Correct Cx26 Delivery In Support Cells Using GT-GJB2 Flag In NHP
Correct Cx26 Delivery In Support Cells Using GT-GJB2 Flag In NHP • Expanded knowledge of targeted cells populations in NHP • No expression in HC confirmed • No morphological defects observed 3 and 9 weeks after intracochlear administration Copyright by Sensorion - 2024 - All Rights Reserved 10
Slide 11: GT-GJB2 Exploratory Toxicity and Biodistribution Study in NHP
GT-GJB2 Exploratory Toxicity and Biodistribution Study in NHP Study design Study results • N=4, M/F, juvenile at • GT-GJB2 is well tolerated and did not surgery induce any macroscopic/organ weight changes or local/systemic • 2 timepoints (1M, 3M) microscopic findings • Normal cochlear histology • Sa
Slide 12: GT-GJB2 Exploratory Toxicity and Biodistribution Study in NHP
GT-GJB2 Exploratory Toxicity and Biodistribution Study in NHP Study design Study results • N=4, M/F, juvenile at • GT-GJB2 is well tolerated and did not surgery induce any macroscopic/organ weight changes or local/systemic • 2 timepoints (1M, 3M) microscopic findings • Normal cochlear histology • Sa
Slide 13: Efficacy in a Mouse Model of GJB2 Deficiency
Efficacy in a Mouse Model of GJB2 Deficiency Proof Of Concept In Progressive Mouse Model Conditional knock-out mouse model leading to 2 phenotypes • GJB2 deletion during or after development ABR threshold - 1 month after birth ABR threshold - 6 months after birth often results in hearing loss and ce
Slide 14: Summary: GJB2-GT Is Moving Into IND/CTA Enabling Studies
Summary GJB2-GT Is Moving Into IND/CTA Enabling Studies CRITERIA GT-GJB2 Broad coverage of cells naturally expressing Cx26, detargeting HC Well tolerated in mice and NHP Limited off-target tissue biodistribution Surgical approach developed and mastered by ENT surgeons Hearing rescue in mice models a
Slide 15: Acknowledgements
Acknowledgements Arnaud Giese Anne-Gabrielle Harrus Crystel Bonnet Jerome Nevoux Rafik Boudra Pauline Liaudet Anne-Valérie Heritier Ghizlene Lahlou Lise Barrot Guillaume Olivier Nawel Mekdad Emilie Bousquet Anais Pages Amrit Estivalet Christine Le Bec Géraldine Petit Andrea Lelli Audrey Broussy Sand
Slide 16: Thank You
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