The Great Story of Gene Therapy

and follow us on: Are you ready to see more about Gene Therapy? Check the Revvity website https://www.revvity.com/ References Gene Therapy Industry Report 2021. Labiotech. June 2021. Jef Akst. Targeting DNA. The Scientist. | Lucy Reading-Ikkanda. Delivering New Genes. June 2012. Ansar Karimian et al. CRISPR/Cas9 technology as a potent molecular tool for gene therapy. Journal of cellular Physiology. January 2019. For a complete listing of our global offices, visit www.revvity.com Copyright ©2023, Revvity, Inc. All rights reserved. 1207959 Revvity, Inc. 940 Winter Street Waltham, MA 02451 USA www.revvity.com Significant advancements Scene 1 over the last decade 1989 First approved protocol to use gene transfer into humans 2003 The complete sequence of the human genome is identified 2009 Intensive research to increase vector safety 2016 First ex-vivo gene therapy approved 2019 First gene therapies approved for the treatment of SMA (Zolgensma) and β-thalassemia (Zynteglo) 1972 Gene therapy concept is discovered by Friedmann and Robin 2008 First adenovirus gene therapy complete phase III clinical trial 2012 First gene therapy approved in Europe 2017 First gene therapy approved in the USA 1990 First clinical trial to deliver a therapeutic gene is achieved in the USA Sensitivity Robustness Sample availability Selectivity Sample stability Challenges Oncology >1400 >400 Neurological Disorders >300 Genetic Disorders >350 Others Therapeutic areas Approaches Replacing A mutated gene Inactivating A mutated gene Introducing A new gene > 2400 Product candidates >1350 Preclinical >300 Phase I >250 Phase II >50 Phase III 20 approved gene therapies Approaches Replacing a mutated gene Inactivating a mutated gene Introducing a new gene Long term safety Efficacy over time Neutralizing immune responses Manufacturing scale up Evolving regulatory guidance Challenges Oncology >1400 >400 Neurological disorders >300 Genetic disorders >350 Others Therapeutic areas Adenovirus 20% Retrovirus 18% Plasmid DNA 17% *Adeno-associated virus AAV* 8% Lentivirus 7% Others Vectors Adenovirus 20% Retrovirus 18% Plasmid DNA 17% *Adeno-associated virus AAV* 8% Lentivirus 7% Others Vectors Scene 2 Major key facts in gene therapies Cell with a mutated gene Production of a mutated protein Diseases Gene therapy Can correct these mutations How does gene therapy Scene 3 work ? By using CRISPR/CAS9 8,659 Mutated cell Identification of the mutation responsible for the disease Creation of a strand of guide RNA that matches the mutated DNA sequence Cas9 cuts, nicks or targets the affected sequence The guide RNA identifies the mutated DNA Guide RNA Cas9 Addition of target gene DNA Non-homologous End-joining Gene knockout Base substitution Prime editing Adenine/ Cytosine base editor RT enzyme Gene replacement Gene repair Gene silence Nonintegrating viruses Integrating viruses Oncolytic viruses By using viral vectors The great story of gene therapy Virus enters in the cell Conversion into DNA Functional protein expressed DNA is integrated into nuclear genome Adeno-associated virus (AAV) Therapeutic DNA Therapeutic DNA Oncolytic virus Lentivirus Therapeutic RNA Virus enters in the cell Endosome breaks down Functional protein expressed Virus binds to the cell nucleus Virus preferentially infects tumor cells Virus replicate within the cell Tumor lysis IN VIVO ex vivo