Big deal: Flagship puts $25M into functionalized red blood cells
Hello world, it’s been some time. First, there was such a silence on the biotech VC market that I actually emailed CrunchBase to get me access to their latest API version to fetch some data— would have made hell of a post, like ‘WE’VE RUN OUT OF INVESTABLE COMPANIES IN BIOTECH!!!111". Then we’ve been busy launching our new firm — check it out, by the way (http://www.4biocapital.com)
And now — kaboom. Eight big deals in a week, enough to last me a couple. Subscribing to a risk of being called a Flagship Fanboy I will still make their story the first one I cover in this batch. Hence, enter Rubius Therapeutics.
Rubius is a company fresh out of the stealth mode in Flagship Labs. It’s built on the IP coming out of the Lodish lab in MIT (yes, that very one Prof Harvey Lodish who wrote your (and mine) Molecular Cell Biology textbook).
In short, Rubius is creating programmable red blood cells to (potentially) treat any auto-immune, allergic and genetic disease.
Erythrocytes (or red blood cells) are pretty unique. As the carriers of oxygen in the body they get into pretty much everywhere — as all of our cells require a steady oxygen supply to function. This means they can potentially deliver any molecule that can bind to them (or enter them) to any part of the body. Some parasites and pathogens specialize on hijacking them for a ride (the malaria Plasmodium sp. being the most famous).
This means RBCs are ideal for delivering stuff one would like them to. There are a couple of problems though: a lot of stuff (like any D/RNA based therapeutics) does not survive long in the plasma; some small molecules tend to decrease the RBC performance. How do we make them to perform a therapeutic function?
There is potential for one answer in the way the erythrocytes are ‘made’. This happens during a process called erythropoiesis. Early precursor cells get activated by eryhtropoietin (a peptide that is often taken as a doping — as it induces RBC maturation) and turn into progenitor cells — erythroblasts. These undergo radical differentiation, losing their nuclei (with the DNA and all the machinery) and becoming little more then blobs stuffed with hemoglobin — in other words, erythrocytes.
As RBCs contain no DNA one can make the progenitor cells transgenic (and maintain them as a culture). This requires a tremendous amount of knowledge about the molecular biology and signalling of the maturation cascade. A plethora of information on this has become available in the last twenty years (with quite a substantial impact from Prof Lodish lab) and it’s high time to commercialize it.
Rubius is building on the Lodish lab ability to cultivate the progenitor cells and make them transgenic through a very rapid ‘plug-and-play’ process. A significant advantage of this approach is that the RBCs themselves carry no genes; therefore any transgenic protein expressed by the progenitor cells will be carried and stored, but the genetic material cannot spread in any way.
The most exciting option is to start expressing extracellular proteins that are exposed on the erythrocyte membrane. This enables three main therapeutic approaches I can think of:
- put a large complex of an (external or internal) antigen plus an array of service proteins to induce T-suppressor driven targeted tolerance (i.e. suppress the immune reaction against a single antigene; think multiple sclerosis, rheumatoid arthritis, allergy, may be ALS). Disadvantages: some T-suppressor therapies very close to the market and might be quite effective (see LON:CIR).
- put an antibody (plus may be a payload) and let the erythrocyte detect and bind pathogens (think infection and antivirals especially) and/or cells that have to be killed (think soluble tumours). Disadvantages: a lot of antibody conjugates already on the market.
- put an enzyme. You get a tiny bio-robot that happily swims around the body converting a molecule you would like to remove into something palatable. An analog of a functional moving bean with a lot of immobilized functional enzymes. A huge win for metabolic diseases.
Judging by the publicity, Rubius is going mainly down the third route, with phenylketonuria (PKU) as their primary indication. This is a relatively common but orphan genetic disease caused by the inability of the body to process an native amino acid phenylalanine. Patients have to go on a very restrictive diet (or develop severe neurological abnormalities and other malformations).
The largest hurdle I see is dosing and maintenance. Should they plan to inject the progenitor cells, engrafting would be desirable but the regulators highly dislike it. If they are going for a regular (every 120 days) top-up of the individuals’ own erythrocytes this will be exorbitantly expensive.
Flagship have put $25M in and says the company is very close to the start of the clinical trials. Very exciting.
Round on CrunchBase: http://bit.ly/1NQ0pyT
Company website: http://www.rubiustx.com/
