Editas Medicine, Inc. · NASDAQ:EDIT

Editas Medicine — Technical Presentation (November 2022)

15 slides from Editas Medicine's technical presentation, Nov 2, 2022

  1. Slide 1: A Mutation-Independent CRISPR/Cas9-Based 'Knockout and Replace' Strategy to Treat RHO-adRP

    A Mutation-Independent CRISPR/Cas9-Based ‘Knockout and Replace’ Strategy to Treat Rhodopsin-Associated Autosomal Dominant Retinitis Pigmentosa (RHO-adRP) Chi-Hsiu Liu, Pavlina Wolf, Ruhong Dong, Yan Huang, Diana Tabbaa, Eugenio Marco, Brian Duke, Andrea Pinilla, Asha Pant, Racheal D’Souza, Judith Ne

  2. Slide 2: Disclosure

    Disclosure The speaker and the co-authors are employees and stockholders of Editas Medicine. 2

  3. Slide 3: Autosomal Dominant Retinitis Pigmentosa (adRP)

    Autosomal Dominant Retinitis Pigmentosa (adRP) • An inherited autosomal dominant retinal disease leading to blindness in later life • Symptoms: o Decreased night vision (nyctalopia) o Loss of peripheral vision (tunnel vision), and eventually significant decline in central vision • No approved treatm

  4. Slide 4: Rhodopsin-Associated adRP (RHO-adRP)

    Rhodopsin-Associated adRP (RHO-adRP) Rhodopsin (RHO) • A light-sensitive receptor protein involved in visual phototransduction in rods • Located in the outer segments of rods • Approximately 30% (US and UK) of adRP caused by RHO dominant mutations • Prevalence: 7,500 patients in US and 12,100 patien

  5. Slide 5: EDIT-103: Dual AAV-Based "Knockout and Replace" Therapeutic Strategy

    EDIT-103: Dual AAV-Based “Knockout and Replace” Therapeutic Strategy • Agnostic to any RHO mutation – thus will knockout any dominant gain-of-function rhodopsin mutant • Step 1: Both mutant and normal endogenous RHO will be knocked out in the treated area • Step 2: Exogenous normal RHO (resistant to

  6. Slide 6: The RHO Promoter Restricts Gene Expression to Rod Photoreceptors in the Mouse Eyes

    The RHO Promoter Restricts Gene Expression to Rod Photoreceptors in the Mouse Eyes AAV5-RHO-GFP RHO promoter GFP IS/OS ONL OPL INL Cone arrestin GFP Merge Scale bar = 20 μm AAV, adeno-associated virus; GFP, green fluorescent protein; INL, inner nuclear layer; IS/OS, inner/outer segments of photorece

  7. Slide 7: EDIT-103 is Highly Specific: No Detectable Off-Target Editing

    EDIT-103 is Highly Specific: No Detectable Off-Target Editing NO OFF-TARGET EDITING AT OFF-TARGET CANDIDATES (rhAmpSeq verification in human retina explants transduced with EDIT-103) 100.00% 50.00% EDIT-103 gRNA Editing (floored to 0.01%) 20.00% 10.00% (On-Target) 5.00% +/- 2bp 2.00% 1.00% 0.50% 0.2

  8. Slide 8: EDIT-103 in Humanized mRhohRHO/+ Mice: Rapid and Stable Gene Editing

    EDIT-103 in Humanized mRhohRHO/+ Mice: Demonstrates Rapid and Stable Gene Editing Editing hRHO mRNA replacement Level of coRHO mRNA‡ 50 105 Dose escalation Editing (%) in rods† 40 104 30 103 20 102 10 0 101 Vehicle 1E11 3E11 1E12 3E12 6E12 9E12 1E11 3E11 1E12 3E12 6E12 9E12 • >25% of rods are edited

  9. Slide 9: EDIT-103 in Non-Human Primates: Approximately 100% Editing in Transduced Photoreceptors

    EDIT-103 in Non-Human Primates (NHPs): Approximately 100% Editing in Transduced Photoreceptors EDIT-103 (KO and Replace) x 125 RHO promoter SaCas9 Editing (%) in rods† 100 gRNA gRNA U6 U6 RHO promoter coRHO 75 Knockout (KO only) x 50 RHO promoter SaCas9 25 gRNA gRNA U6 U6 Stuffer 0 Vehicle KO EDIT-1

  10. Slide 10: EDIT-103 in NHPs: Knockdown of Endogenous RHO and Over 30% Protein Replacement

    EDIT-103 in NHPs: Nearly Complete Knockdown of the Endogenous RHO and Over 30% RHO Protein Replacement RHO mRNA RHO Protein % of NHP RHO Protein‡ 150 150 % of NHP RHO mRNA† • 80% and 90% knockdown of Endogenous 100 100 NHP RHO endogenous NHP RHO mRNA levels 50 *** *** 50 achieved at 3E12 and *** ***

  11. Slide 11: RHO Protein Expression and Retina Morphology Preserved in EDIT-103-Treated NHP Retinas

    RHO Protein Expression and Retina Morphology was Preserved in EDIT-103-Treated NHP Retinas Compared with KO-Treated Retinas RPE Vehicle KO (3E12 vg/ml) EDIT-103 (3E12 vg/ml) IS/OS IS/OS IS/OS ONL ONL ONL RHO protein / Cas9 genome IS/OS IS/OS IS/OS ONL ONL ONL (ONL) H&E staining AAV ratio: 1:1; Injec

  12. Slide 12: Retina Function Preserved in the EDIT-103-Treated NHP Eyes

    Retina Function Preserved in the EDIT-103-Treated NHP Eyes Compared to the KO Only Treated Eyes Retinal layers a-wave b-wave RPE 150 150 IS/OS % of a-wave† % of b-wave† a-wave ONL 100 100 OPL INL b-wave 50 50 IPL GCL 0 0 Vehicle KO EDIT-103 EDIT-103 Vehicle KO EDIT-103 EDIT-103 NFL 3E12 3E12 6E12 3E

  13. Slide 13: Summary

    Summary EDIT-103 is a one-time, high efficacy, mutation-agnostic gene medicine to permanently suppress the toxic gain-of-function associated with RHO-adRP Ex vivo: EDIT-103 shows high specificity in human retinal explants In vivo: • mRhohRHO/+ mouse: o EDIT-103 achieved rapid and stable gene editing

  14. Slide 14: Acknowledgements

    Acknowledgements Mariacarmela Allocca Asha Pant Ruhong Dong Andrea Pinilla Racheal D’Souza Mark S. Shearman Brian Duke Diana Tabbaa Georgia Giannoukos Adrian Timmers Yan Huang Pavlina Wolf Eugenio Marco Kate Zhang Judith Newmark * Alphabetical order according to last names 14

  15. Slide 15: Thank you

    Thank you

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