Gene-Edited Cell Therapies
Cell therapy is the infusion or transplantation of modified human cells into a patient for the treatment of a disease. The origin of the cells can be from the patient (autologous) or from a healthy donor (allogeneic).
Using zinc finger nuclease (ZFN) genome editing technology, Sangamo is developing autologous and allogeneic gene-edited cell therapies for blood disorders including beta thalassemia and sickle cell disease, immunological disorders, as well as various types of cancer. These programs draw upon years of experience in manufacturing of cell therapies from our foundational T-cell and hematopoietic stem cell (HSC) programs in HIV, which were the first ex vivo genome editing products to enter human clinical trials.
ex vivo genome editing with zfns
Sangamo’s cell therapy platform employs ZFN genome editing technology ex vivo (outside the body) to edit human cells for therapeutic use. The cells are collected from the patient (autologous approach) or from a healthy donor (allogeneic approach) and shipped to a cGMP manufacturing facility specialized in the production of cell therapies.
ZFNs can be used to either knock out or insert genes, or both, in human cells to treat a specific disease. A pair of ZFNs is needed to edit (knock out or insert) a single gene. Sangamo can also deliver multiple ZFN pairs to make multiple gene edits simultaneously, a technique called multiplex editing.
Knocking out genes
For ex vivo gene editing, Sangamo delivers ZFNs to cells as messenger RNA (mRNA) using a non-viral delivery technique called electroporation. The mRNA provides the cell with instructions on how to make the ZFNs. Once made, the ZFNs target and knock out a specific gene or sequence of DNA.
To insert a gene, ZFNs are delivered by electroporation of mRNA and an adeno-associated virus (AAV) vector is used to deliver a therapeutic DNA sequence, the "transgene" to the cell. Once the ZFNs make a precise cut at a target site in the cell’s genome, the transgene is inserted into that site to enable the production of a protein receptor to be expressed on the cell’s surface.
MANUFACTURING AUTOLOGOUS CELL THERAPIES FOR HEMOGLOBINOPATHIES
This diagram represents Sangamo’s approach to ex vivo gene-edited cell therapy using ZFNs for beta thalassemia. In partnership with Sanofi, we are pursuing a similar approach for sickle cell disease.
MANUFACTURING TREG BASED AUTOLOGOUS CELL THERAPIES
Regulatory T-cells (Treg cells or Tregs) are a type of white blood cell which play a key role in regulating immune response and inflammation. Sangamo is evaluating the potential of CAR-Tregs (Tregs genetically modified with a chimeric antigen receptor, or CAR) for the development of therapies for immunological diseases, such as Crohn’s disease and multiple sclerosis, as well as for the prevention of immune-mediated rejection in a solid organ transplantation setting.
UNIVERSAL T-CELL THERAPIES
Modified T-cells have demonstrated success in treating blood-based and other rare forms of cancers. However, to treat more common cancer types, an off-the-shelf, or allogeneic, therapy is a more practical solution. Such universal cell therapies can be quickly administered to any patient upon diagnosis rather than having to wait precious weeks to harvest and manufacture cells for each individual patient.
Using our zinc finger nuclease genome editing technology to knock out genes that identify these cells as foreign to the person receiving them, we are working not only to make the possibility of universal cells a reality, but also to enable additional quality controls that aren’t possible with current autologous therapies.
In a single step, we can multiplex several edits to the harvested T-cells at a highly efficient rate. These gene modifications include knocking out the cell’s native genes that would lead to graft vs host disease (GvHD) or elicit a host immune response, while simultaneously inserting a therapeutic gene into a precise location in the cell’s DNA to express a receptor on the cell’s surface to specifically identify and bind to the target cancer cells. Sangamo’s ability to make these modifications at the same time allows for a cheaper and faster manufacturing process and greater consistency of gene-edited T-cells in an allogeneic cell therapy.
In addition to effector T-cells, Sangamo is also investigating this approach with regulatory T-cells (Tregs).