archives –––––––– @btnaughton

Natural Knockdowns: myostatin

Let's say you want to create an therapeutic antibody against a protein. Typically, you start by immunizing an animal with the protein (antigen) of interest, and harvesting the antibodies that the animal creates in response. Then you "humanize" the antibody (replace parts of animal IgG with human IgG) and start testing in humans. Although this method (and many permutations) has been working well for many years, there are still unpredictable effects, and an antibody developed in this way is far from assured to be safe and effective.

myostatin

Recently, companies like X01 have shown the value of using "fully human" antibodies as therapies. X01 started with an anti-thrombin antibody isolated from a patient with an unusual clotting phenotype. They turned this antibody into an anticoagulation therapy and sold it to J&J this year.

So to generalize, instead of immunizing an animal with your antigen, you can try to find a human with the unusual phenotype you want and develop an antibody that way. The major putative advantage is that you start off with a free n-of-one human experiment showing that your therapy is safe and effective. The problem changes from one of biochemistry to bioprospecting.

PCSK9

Human genetics is playing an increasingly important role in drug development, especially in helping determine the best drug targets. The most famous example of this is the gene PCSK9, which, when homozygous null, results in very low LDL, excellent cardiovascular health, and no apparent side-effects. After its discovery, several pharma companies immediately began developing therapies against this target. This discovery also likely played a part in Amgen buying DeCode, Regeneron's huge human genetics effort, and Robert Plenge (@rplenge) joining Merck. For an excellent summary of the PCSK9 story, see this excellent talk by Jonathan Cohen.

Natural knockdowns

So we know that fully human antibodies have very attractive properties, and we know that human genetics can help us find useful targets. Can we combine the two? George Church sometimes shows a slide listing many of the known protective mutations. These genes are mostly full knockouts (nulls) and, perhaps surprisingly, these broken genes are sometimes beneficial.

myostatin

Knockdowns are similar to knockouts, except here the protein is made correctly but then suffocated by something else, like an antibody. (Knockdowns normally refer to inhibition at the nucleotide level, but the term seems to fit better than the alternatives.) Natural knockdowns would present similarly to human knockouts, except that they would not be present at birth, but would develop later in life. In other words, these are unusual autoimmune diseases.

Myostatin

After going through various lists of beneficial knockouts, one stands out: myostatin. Myostatin is an inhibitor of muscle growth, so the knockout results in a muscular phenotype. There is at least one known homozygous null human, an extremely muscular German toddler. In the animal kingdom, there are several examples, including the Belgian Blue cow.

myostatin

A natural knockdown of myostatin would theoretically result in unexpected muscle development, perhaps late in life, and without a change in lifestyle.

A myostatin knockdown fulfills my criteria:

  • It is an extracellular protein The protein must be accessible by antibodies.
  • It has an obvious therapeutic application Myostatin antibodies are potentially a treatment for many muscle-wasting diseases. There are already several in development by a number of companies (e.g., Pfizer, BMS).
  • It has a measurable phenotype Greatly increased musculature is pretty easy to measure, perhaps even easier than LDL.
  • The phenotype is benign This is not completely necessary, but it is an attractive property in terms of safety that the antibody does not cause another disease.

Of course, it is not trivial to find a person with this unusual phenotype — if they even exist — but if we could, then they might by carrying an extremely useful therapy in their blood. If you know someone who has added a lot of muscle quickly and cannot explain why, let me know!


Comments


Boolean Biotech © Brian Naughton Powered by Pelican and Twitter Bootstrap. Icons by Font Awesome and Font Awesome More