JUL 22, 2021 4:15 PM EDT

Clinical Scale Gene Editing for Cell and Gene Therapy Applications

C.E. Credits: P.A.C.E. CE Florida CE
Speaker

Abstract

Genome editing technologies have enabled the precise manipulation of DNA sequences at targeted sites to achieve therapeutic effects. Engineered endonucleases like CRISPR-Cas9 institute site-specific DNA breaks to either knock out a gene or enhance the homology directed repair (HDR) based gene correction with an intact donor template. High-fidelity editing, multiplexing capacity, and the ease of implementing the CRISPR-Cas9 system have expanded the scope of programmable genetic manipulations to include simultaneous deletions or insertions of multiple DNA sequences in a single round of mutagenesis. Gene editing has many applications in basic and biomedical research, including disease modeling. A promising cell therapy approach for hemoglobinopathies or cancer immunotherapy involves the ex vivo gene editing of autologous hematopoietic stem cells (HSCs) or T cells before administering patients. For hemoglobinopathies, gene editing tools like CRISPR-Cas9 can be used to install a double stranded break to either knock out a gene like BCL11A or enhance the knock-in with an intact donor DNA template to correct the mutation in the beta subunit of the hemoglobin gene (HBB). Cancer immunotherapy applications use CRISPR-Cas9 to knock out the TCR locus or checkpoint modulators to improve the efficacy and clinical outcomes of the living drug. Here, we describe the use of a clinically validated, regulatory compliant, scalable electroporation platform for the high efficiency, low toxicity gene editing of hCD34+ hematopoietic stem cells (HSCs), T cells, and iPSC cells at a clinical scale for preclinical evaluation and commercial production of cell therapy products for Sickle Cell Disease, TCR therapy or in disease modeling.

Learning Objectives:

1. llustrate therapeutic level of gene correction of the SCD mutation in patient derived CD34+ HSCs cells by electroporation of CRISPR-Cas9 gene editing tools. The gene edited cells with homology directed repair (HDR) engrafted and were detectable for a significant period of time in mouse xenograft models.

2. Paraphrase the optimization of the RNP mediated genome editing using CRISPR-Cas9 and a ssODN template to engineer iPSCs for treatment of diseases like DMD and Miyoshi Myopathy.

3. Describe a clinical trial where patients were infused with an autologous CRISPR-Cas9 genetically edited CD34+ HSC commercial product aimed knocking out the BCL11A enhancer, thereby reactivating the production of fetal hemoglobin to alleviate the debilitating symptoms of SCD and beta thalassemia.


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