Auxolytic has developed a nutrient-based safety-switch for cell therapies that doesnt rely on introducing transgenes. The process, auxotrophy, uses the engineered inability of an organism to synthesize a compound required for its survival to allow physicians to turn off a gene therapy if serious side effects develop.
The work currently is in preclinical phases, in humanized cells in mice, and appears promising. When it advances to clinical applications, patients receiving cell therapies (such as CAR T, stem cell, and TCR therapies) containing this safety switch would be given supplements of a particular nutrient uridine, in this case. If the cell therapy went awry, patients could simply stop taking the uridine supplement and the cellular therapy would cease to function.
A paper published in Nature Biotechnology describes how the off switch could be engineered into cell therapies. Basically, it says, the approach knocks out the gene that disrupt(s) uridine monophosphate synthetase (UMPS) in the pyrimidine de novo synthesis pathway in cell lines, pluripotent cells, and primary human T cells.
This knockout makes proliferation of the cell therapy dependent on the external supply of uridine. Therefore, researchers can control cell growth by modulating the uridine supply in vitro and, importantly, in vivo after transplantation.
In the movie Jurassic Park, the dinosaurs were engineered to need lysine. If they escaped, there was no lysine to keep them alive. This therapy is very similar, founder and CEO James Patterson, M.D., Ph.D., told BioSpace.
Rather than lysine, Auxolytic uses uridine as the controlling nutrient. Uridine is important in carbohydrate metabolism and is found in yeast, tomatoes, broccoli, sugarcane and other foods, and also can be produced by the body when inadequate amounts are consumed in the diet.
The quantities available through the diet or produced by the body, however, arent high enough to sustain the engineered cells, Patterson said. Evidence comes from a rare genetic disease, orotic aciduria. Patients with that condition have a mutation in the UMPS gene that causes them to produce insufficient levels of the enzyme that breaks down orotic acid. They often die at very young ages if not supplied with quantities of pure uridine. This shows that a normal diet wont compensate.
Patients of cell therapies that incorporate Auxolytics nutrient-based safety switch likely would be able to eat their usual foods, but with nuridine added as a supplement. The approach Dr. Patterson developed hasnt been tested in patients yet.
This is the same nutrient I worked with in yeast, but now in human cells, Patterson said. Early work shows that only the engineered cell therapy would be affected by uridine modulation. Within one week of withdrawing the uridine, the engineered cells were inactive and unable to proliferate. Normal cells continued to function as usual.
At age 27, Patterson already has worked with many of the thought leaders in medicine and biomedical research while pursuing his M.D. and Ph.D. degrees at the University of Cambridge and the Francis Crick Institute. Beginning early during his university days, he performed research placements at the University of Zurich, The Gurdon Institute, The Whitehead Institute and The Cambridge Stem Cell Initiative.
This nutrient-based approach to controlling cell therapy is the direct result of that body of experience.
During my M.D./Ph.D. training, I became interested in cell therapy and its potential for curing patients, but there were safety risks. My Ph.D. work focused on yeast biology, studying how cells control their size. There, the idea of nutrient-based cell control was commonplace, but no one was working on this in human cells, he said. I became interested in science when I was very young, so during my undergraduate work I made sure I was thinking about the science being done in the labs in addition to what I was learning in lectures. Theres a difference.
Lectures lay the scientific foundation, but lab work is cutting-edge and forward-thinking.
I started working in labs when I was 19 in Zurich. I spent all my summers working in labs, asking a range of questions and working in lots of different systems, Patterson said.
Such broad exposure proved foundational for Auxolytic.
As you can see, this is a yeast technology. Thats not where you usually go to look for cell therapy ideas, he added.
He advises students early on to get into exciting labs that are doing interesting, fundamental science. Ask basic questions of how cells work, for example. You never know what youll find that could be applicable to the clinic. Jumping to clinical research (too early) causes you to lose the blue sky thinking.
Auxotyic, based in Cambridge, UK, is, for now, a virtual company of onebut with ample advisors.
Theyve helped along the way in the academic sector and also in the management of business, Patterson said. Those mentors include seasoned industry veterans who know what it takes to take a drug from bench to bedside, and who understand patenting and licensing.
The next step for Auxolytic, scientifically, is to identify potential applications around selecting for differentiated cells from induced pluripotent stem cells (iPSCs). Much of the scientific work is being done in collaboration with the Matthew H. Porteus lab at Stanford University.
On the business side, he continued, Were excited to get this into the hands of big cell therapy companies that currently are making cell therapies without a safety switch. Were looking to partner with them to get this to patients.
Auxolytic is talking with several interested companies. People recognize the need for a safety switch and are very excited, Patterson said. Discussions are going well.
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Auxolytic’s Nutrient-Based Shut-Off Switch Boosts Cell Therapy Safety Without Transgenes – BioSpace