Last year the M.D. Anderson Cancer Center started a Phase I clinical trial for a very interesting peptide based drug on the power of the counterintuitively awesome paper that I’m going to present today. If it works in humans as well and as safely as it does in three other Old World primates it has the potential to be a game changer for the treatment of metabolic syndrome; the primary driver of obesity, Type II diabetes, and heart disease.
A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys
KF Barnhart, DR Christianson, PW Hanley, et al. Published 2011 in Sci Transl Med. DOI: 10.1126/scitranslmed.3002621 [REQUIRES FREE SUBSCRIPTION]
Obesity, defined as body mass index greater than 30, is a leading cause of morbidity and mortality and a financial burden worldwide. Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Biological differences between rodents and primates are a major hurdle for translation of anti-obesity strategies either discovered or developed in rodents into effective human therapeutics. Here, we evaluate the ligand-directed peptidomimetic CKGGRAKDC-GG-D(KLAKLAK)2 (henceforth termed adipotide) in obese Old World monkeys. Treatment with adipotide induced targeted apoptosis within blood vessels of white adipose tissue and resulted in rapid weight loss and improved insulin resistance in obese monkeys. Magnetic resonance imaging and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue. At experimentally determined optimal doses, monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans.
The basic idea behind this paper started when cancer researchers looking for markers on blood vessel walls they could use to target cancer found a peptide that would specifically bind to markers found only on the blood vessels that supply adipocytes, the cells that generate and maintain fat stores. Figuring that this might be useful for tackling obesity they made that targeting peptide sequence but with a second sequence known to cause cell death shoved onto it. Thus, when injected into mice, it would bind specifically to the cells of those blood vessels that were supplying fat cells, internalize into those cells, and destroy the mitochodria, killing those blood vessels and starving the fat cells. Now adipocytes are serious endocrine regulators that do a heck of a lot more than make you fat, logically this should be wreaking all kinds of havoc with the loss of regulatory function much less all the now unshepherded fat and dead adipocytes overwhelming the liver and kidneys as waste. Indeed they regulate how much fat gets stored and released as well as what kinds of fats get stored and released, they are central to the insulin pathway that regulates blood sugar, they play a role in blood clotting, and heck they are even significantly involved in creating sexual dimorphism. However, these monkeys did shockingly well. The treatment did not seem to cause particularly bad side effects, they only noticed some renal toxicity (meaning somewhat bad for kidneys) and that was reversible, presumably from the kidneys needing to clear out waste in the bloodstream from the cells. Intuitively, I would not have expected mice to live, much less primates, but there you go, this is science in action.
The really cool finding is not so much the weight loss but the increase in insulin resistance which indicates that this drug could actually address the epidemic of metabolic syndrome that is behind so much of the obesity in this country. It has the potential to be a game changer, particularly if the total number of viable adipocytes that is affected by this treatment addresses other problems like the insufficient satiety and chronic fatigue that make healthy diet and exercise that much more difficult for many.
Of course there is a decent chance that there are subtle things that can go wrong in environments unlike the monkeys’, in people with odd physiologies, or with weird drug interactions, but the idea would be that anything along those lines would be figured out in trials – the Phase I portion of which is projected to be complete by 2016.