http://www.forbes.com/sites/luketimmerman/2015/12/09/tweaking-red-blood-cells-into-drugs-rubius-snags-25m-from-flagship/
Luke Timmerman, December 9th, 2015
Cell therapy is one of the big ideas in biotech. Entrepreneurs have become captivated by possibilities of engineering white blood cells so they can be re-infused into patients and fight cancer.
One startup in the Boston area is seeking to pull off a similar trick, but for red blood cells.
Rubius Therapeutics, the latest hatchling from the incubator at Cambridge, Mass.-based Flagship Ventures, is announcing today it has secured $25 million from the venture firm to further develop its technology and initially apply it toward a rare metabolic disease in children—phenylketonuria (PKU). As is usually the case with Flagship, it has rallied big names for this cause. Harvey Lodish of the Whitehead Institute, MIT’s Robert Langer, Merck chief medical officer Michael Rosenblatt, and former FDA chief counsel Peter Hutt are among them.
The dream at Rubius goes something like this. It takes blood-forming stem cells from a universal (O-negative) blood donor off the shelf, and inserts genes for making certain enzymes. For three weeks, the cells are cultured in the lab. The gene gets into the nucleus of the developing blood cell, and starts making the enzyme of choice before the red blood cell matures and naturally spits out its nucleus. What’s left are what Rubius calls enzyme of choice before the red blood cell matures and naturally spits out its nucleus. What’s left are what Rubius calls “functionalized red blood cells” which can be infused, and which ought to avoid being killed by the immune system. At least in theory, those tiny red blood cells, just 8-10 microns in diameter, can live as long as four months in the body. If the cells can express the desired enzyme, and the red cells can last that long in the body, they could make a worthwhile product.Rubius, which started about 18 months ago at Flagship, has shown that it can make 50 different types of the genetically modified red blood cells so far, Kahvejian said. Phenylketonia rose to the top of the company’s drug development priority list. That’s because phenylketonuria is a disease characterized by excessive buildup of the amino acid phenylalanine in the blood, and the company has shown that its modified red blood cells, made to express a certain (undisclosed) enzyme, can chop up and break down the excessive amounts in blood samples from PKU patients. Similar levels of phenylalanine degradation were seen when the modified red blood cells were given to live animals, Kahvejian said. The feat hasn’t yet been accomplished in multiple species of animals, he said.
There’s no question about the need for treatment in PKU. Patients with the disease, from a very early age, have to live with a highly restrictive diet to keep them from suffering too much phenylalanine buildup or else risk developing severe mental retardation. Biomarin Pharmaceutical currently markets a pill for called tetrahydrobiopterin (Kuvan), but it’s only modestly effective for a subset of patients.
“The question to me is whether you can get enough of the Rubius drug,” said Rick Stead, a hematologist and clinical/regulatory consultant with Biopharma Consulting Service in Bellevue, Wash. who hasn’t done business with Rubius. “It’s an intriguing approach. But how much will be enough for a given disorder, and how often will they need to be infused?”
Red blood cells naturally have some interesting properties for drug development. Their ability to last as much as four months in the body potentially can translate into relatively infrequent infusions. Scientists have recently begun to learn more about the interplay between red blood cells and other cells of the immune system—specifically how red blood cells can tamp down an excessive reaction against certain protein structures. Red blood cells also are unusual because they don’t have a nucleus. From a drug development standpoint, that means you know what kind of dose you’re giving the patient, and can take comfort in the fact that the cells aren’t going to grow and divide out of control in an unpredictable manner. That’s been one concern with cell therapies for cancer. Engineered T-cells of the immune system have the ability to grow and proliferate in the body to attack cancer cells, but sometimes to an excessive degree that causes serious side effects.
Red blood cells naturally have some interesting properties for drug development. Their ability to last as much as four months in the body potentially can translate into relatively infrequent infusions. Scientists have recently begun to learn more about the interplay between red blood cells and other cells of the immune system—specifically how red blood cells can tamp down an excessive reaction against certain protein structures. Red blood cells also are unusual because they don’t have a nucleus. From a drug development standpoint, that means you know what kind of dose you’re giving the patient, and can take comfort in the fact that the cells aren’t going to grow and divide out of control in an unpredictable manner. That’s been one concern with cell therapies for cancer. Engineered T-cells of the immune system have the ability to grow and proliferate in the body to attack cancer cells, but sometimes to an excessive degree that causes serious side effects.
Like any startup, Rubius has a lot of work ahead. It’s also not the only group that’s thinking about how to deliver certain proteins into cells for re-infusion. Gaithersburg, Maryland-based MaxCyte is one company that uses electroporation to essentially zap cells to allow certain molecules to pass inside. SQZ Biotech, an MIT spinout, struck a partnership with Roche this week to further apply its technology for “squeezing” certain engineered functions into B cells of the immune system to make them better at wiping out cancer when re-infused.
“The next challenges for Rubius will be to demonstrate that this modality is safe and efficacious in man, and to assess how broad its applicability will be,” said Lodish, a scientific co-founder of Rubius. “With this done, the Red-Cell Therapeutic platform will prove to be a valuable new tool to fight a great number of diseases.”
Rubius, which draws its name from the Latin word for “red,” has 13 employees at the moment, Kahvejian said. With the new cash, it plans to further develop its technology, invest in its manufacturing process for clinical trials, and run the necessary experiments to bring its lead drug candidate for PKU into clinical trials in 2016. One of the key tasks for improving the technology will be to see if Rubius can make red blood cells that can express more complex protein structures, like antibodies and growth factors, both inside and on the surface of red blood cells.