In a comment to yesterday's post, William Knight says:
"While the initial challenges of developing and delivering therapeutic proteins are no doubt far greater, it seems to me that in the long run, proteins, peptides and nucleic acids are the right tools for the job, not small molecule analogues."
Well, I don't quite agree, but he's not the first person to think that way. An awful lot of money has been thrown at the problem of using antisense DNA therapeutically, for example, and I think that a similar amount is in the process of flowing into RNA interference. On the protein front, things have been more successful. There are quite a few protein-based therapeutics out there, starting with insulin and ethythropoetin.
One problem, as he correctly states, is delivery. There have been any number of ingenious approaches to oral delivery of large biomolecules, but there's still no solution in sight. We have enough trouble dosing small molecules and getting them absorbed and distributed; the problems facing large proteins and oligonucleotides are still worse. The gut is designed to rip these things apart, and the gut wall is designed to not absorb them. There are alternate dosing routes, but those are no stroll to riches either, as witness the multiyear campaigns to develop an inhaled form of insulin.
You'd think that biomolecules would be less toxic and more efficacious than small molecules, too - this was one of the early promises of the whole biotech industry. But that's been tricky to realize. A recent example is found with Amgen's attempted use of glial-derived neurotrophic factor for Parkinson's disease. Early results were promising, despite the fact that the protein had to be administered directly into the brain. But things haven't worked out:
"One of the most promising experimental therapies for Parkinson's disease could be shelved after scientists revealed today that a clinical trial has been stopped because of safety concerns. . .Hopes for the treatment soared last year when it was announced that the first five people treated with GDNF experienced a dramatic recovery in their movements. But on Tuesday, Anthony Lang of Toronto Western Hospital in Canada revealed that a second, more extensive clinical trial of GDNF has been halted because the drug showed little signs of working and some potentially dangerous side effects."
Those included neuronal death in monkey studies, and the appearance of antibody responses to GDNF in several of the patients. Raising antibodies to close relatives of your own proteins is not something you want to do. They're still trying to figure out what went wrong - it could be that GDNF was never much good from the start. A five-person trial is capable of producing just about any result under the heavens.
But this illustrates some of the problems. For now, until we understand things much better, biomolecules will have more liabilities than small synthetic ones, and just as good a chance at failure. Perhaps, eventually, the odds will shift.