On May 17, 2023 Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, reported the presentation of new preclinical data that further demonstrated the potential of Prime Editing to correct the causative mutation of chronic granulomatous disease (CGD) and preclinical data that showcased the potential application of the Prime Editing Assisted Site-Specific Integrase Gene Editing (PASSIGETM) platform to generate multiplex-edited CAR-T cells for the treatment of certain cancers and immune diseases (Press release, Prime Medicine, MAY 17, 2023, View Source [SID1234631812]). The data are being presented today during the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 26th Annual Meeting, being held May 16-20, 2023, in Los Angeles, California.

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"We are very pleased to present these new data for our CGD program and PASSIGE platform today at ASGCT (Free ASGCT Whitepaper), which underscore our belief in the breadth and potential of Prime Editing to offer curative treatments for many diseases," said Jeremy Duffield, M.D., Ph.D., Chief Scientific Officer of Prime Medicine. "Our CGD program is progressing well, and with today’s data demonstrating the reproducibility of PM359 to correct the disease-causing mutation in CD34+ cells ex vivo with no off-target editing detected in the comprehensive set of studies done to date, we look forward to the PM359 program’s advancement through Investigational New Drug-enabling studies. Further, while the benefits of autologous CAR-T therapies are well established, their full potential is often hindered by manufacturing and delivery challenges. With our PASSIGE platform, we believe we can create allogeneic products that may overcome these challenges with a one-step, non-viral approach that could expand the applicability of T cell therapies for the potential treatment of tumors and immune diseases."

CGD Presentation Highlights
CGD is a rare inherited disease that leads to recurrent, debilitating and often life-threatening infections. It is caused by mutations in genes, including NCF1, that encode proteins that form NADPH oxidase, an enzyme that kills bacteria and fungi to control infection. Prime Medicine is advancing an ex vivo Prime Editing program that aims to correct the disease-causing mutation in NCF1 in CGD patient CD34+ hematopoietic stem cells (HSCs) and restore NADPH oxidase function. Prime Medicine has previously shared data from the CGD program that demonstrated the ability of Prime Editing to correct a CGD causative mutation in CD34+ cells ex vivo. The Prime Edited CD34+ cells engrafted long-term in vivo with editing levels greater than 92%. Today’s findings added to that, showing:
•Prime Editing was highly reproducible, demonstrating greater than 90% Prime Editing in CD34+ cells from each of four donors
•16-week engrafted Prime Edited CD34+ cells repopulated the bone marrow, reconstituted production of human blood cells, and biodistributed to the spleen and peripheral blood
•Comprehensive off-target analyses demonstrated no detected off-target activity, large deletions or translocations in Prime Edited CD34+ cells
•These findings provide further support for the advancement of the company’s first development candidate, PM359, as a potential treatment for CGD

PASSIGE Presentation Highlights
Prime Medicine is advancing a platform technology known as PASSIGE, which combines Prime Editing with an integrase or site-specific recombinase enzyme to enable the introduction of large-sized cargo into the genome as a potential one-time therapy. This approach is designed to expand the versatility of Prime Editing with the intent to broaden the range of permanent genomic edits that Prime Editing can make to potentially treat disease, including the ability to insert, delete or invert gene-sized pieces of DNA. In today’s presentation, Prime Medicine highlighted expanded work using PASSIGE technology and a non-viral approach to generate CD19 CAR-T cells, as well as
robust disruption of relevant target genes (TRAC and B2M) using Prime Editing in primary human T cells. Results showed:

•Single-step PASSIGE-mediated insertion of a CD19-CAR at the TRAC genetic locus in primary human T cells led to greater than 90% loss of T cell receptor expression and 60% targeted integration of a 3.5 kb CD19 CAR transgene, with no observed impact on T cell viability or T cell expansion
•PASSIGE-generated CD19 CAR-T cells exhibited potent anti-tumor activity in vitro and in vivo
•Prime Editing of the B2M gene in primary human T cells led to greater than 90% knock-out of B2M protein expression
•Efficient multiplex Prime Editing at three genomic target sites in primary human T cells
•These results support the potential of PASSIGE and Prime Editing to provide a modular, one-step system to create best-in-class, potent and targeted, allogeneic CAR-T cell therapies

Presentation Details
Abstract Title: (101) Prime Editing of Human CD34+ Long-Term Hematopoietic Stem Cells Precisely Corrects the Causative Mutation of p47phox Chronic Granulomatous Disease and Restores NADPH Oxidase Activity in Myeloid Progeny
Date & Time: Wednesday, May 17, 2023, 5:15 – 5:30 p.m. PT
Room: Room 515 AB
Session Title: Genome Editing Therapies & Safety I
Presenter: Jennifer Gori

Abstract Title: (602) An All-Prime Editing One-Step Approach for Non-Viral Generation of a Multiplex-Edited Allogeneic CAR-T Cell Product
Date & Time: Wednesday, May 17, 2023, 12:00 p.m. PT
Session Title: Wednesday Poster Session
Presenter: Emily Pomeroy