Today's alert is about recent significant developments in AD. Elan, the Irish pharmaceutical company, has just added more evidence to the kitty that antibodies to the beta amyloid protein can reduce senile plaques in a mouse model of the disease. To refresh--AD is a neurodegenerative disease with two pathological hallmarks in humans. At autopsy brains show both deposition of dense and diffuse plaques made up of beta -amyloid, which is a breakdown product of a larger protein called amyloid precursor protein (APP). The processing of APP is under intense study and at least two enzymes, beta and gamma secretase seem to be critical in order to form the smaller peptide beta-amyloid, which is deposited within in the brain matter but outside of cells. The deposition is in a fibrillar structure known as an amyloid or senile plaque. The other pathological hallmark is a dense tangle inside neurons themselves, called neurofibrillar tangles. One caveat about all the mouse model of AD is that mice only get plaques they don't get the tangles-so it may not be a totally equivalent model from which to draw conclusions. Many other factors can affect the course of the disease, such as ones lipoproteins genotype (certain alleles of apoE are associated with early onset disease). A current debate centers on whether the amyloid plaques are epiphenomena or actually cause neuronal death --some investigators speculate that the neurofibrillar tangles are of primary importance. At this point the debate is tilting towards the amyloid camp in that much of the experimental work in mice indicates a correlation of the disease with the development of plague-however again, in mouse models of AD there are no neurofibrillary tangles. Until a few years ago there wasn't a good animal model which hindered progress however the with the development of transgenic mice expressing a mutant APP (forming plaques more readily) and mice over-expressing one of the secretase (presinilin) genes--we now have our small animal model--and true progress has been rapid.
Anyway back to the main thread of the story--a few years ago Elan started working on a vaccine to produce antibodies to beta-amyloid --it seemed like such a farfetched approach that people working in the field didn't consider it a serious contender. However, skeptics have been converted as continuing mice experiments clearly demonstrate that the disease prone transgenics were protected by vaccination. Sophisticated cognitive studies showed that mice treated with the vaccine were smarter, learned better and that they developed less plaque than untreated controls. However these studies did not show whether plague already present could be cleared. This would be important since presumably any human treatment must not only prevent worsening but also hopefully reverse the process already in place. The recent study in Nature Medicine extends those observations. In the latest experiment antibody applied directly to the brain surface cleared adjacent plaques (it did not clear amyloid vascular deposits). Furthermore the clearing was associated with a microglial (the macrophages of the central nervous system) infiltration. These cells have receptors that bind to the effector portion of an antibody leading to the taking up of the attached b-amyloid and its degradation. All in all the experiments prove that antibodies directed against an epitope of beta-amyloid can clear pre-existing plaque and by inference that antibodies generated by a vaccine might be able to do the same. A further inference is that this may reduce the ongoing neuronal loss. The experiment also opens up the possibility of using a monoclonal antibody to treat the disease--of course you have to get it into the CNS but techniques are available. This approach would mitigate the problem of having to generate an immune response in an older age group, many of whom are already immune compromised and of course it would let us pick out the most effective antibody. Early human trials are under way using the vaccine approach. Other companies are approaching the problem of clearing existing amyloid. Praecis is already in a phase 1 human trial with a small molecule that binds beta-amyloid and promotes clearance via the CSF (cerebrospinal fluid)-at least in one of the mouse transgenic models.
The large pharmaceuticals are also in on the act. Both beta and gamma secretase are necessary to cleave the parent protein into the pathologic peptide. We are well on our way to understanding the genes, proteins and chemistry of these reactions. Amgen is working on finding inhibitors to beta secretase--the transgenic mouse that forms amyloid has been crossed with the beta secretase knockout and the resulting offspring do not form amyloid (evidence of the importance of the beta secretase protein for the formation of plaque)--more important, as far as we can tell the mice are otherwise normal-this may be very a important clue that inhibition of this particular isoform of beta secretase in humans may not have serious side effects-- but only trials will tell. Another favorable sign is that this particular target has lots of similarities to other pharmaceutical targets to which we have developed drugs. Examples of such drugs are the HIV protease and ACE inhibitors--so we're not starting from square one when going after an inhibitor to this particular class of proteases. Bristol Myers is working on inhibitors for the gamma secretase but the genetic experiments in that case are not so benign. Mice are not humans and lots can go wrong making the translation from the small animal model to a human therapy but I think we have a very solid and hopeful start. In my mind this disease is probably the number one problem in an aging population--the suffering caused is enormous, the costs to society are horrendous and anyone living long enough will get it.
There is now real reason to have hope. In tandem with developing new therapies we must have new and early diagnostics--neural thread proteins have been talked about but at this stage there is no clear methodology-we need a sensitive and specific test with a very low false positive rate. I am hopeful that more good news will follow.
biospace.com
Jim |
