First off it was obvious from the Elan trials that suddenly making a protein abundant in plaques in the brain (amyloid beta) into an antigen would lead to inflammation.... what were they thinking!
Immunotherapy has been successfully used in multiple mouse models of AD, including peripheral active and passive immuunisation. But here is the question: Is removing extracellular amyloid plaques in human AD going to cure the disease?? The probable answer is no, more and more researchers are showing that plaques are an end point - a protective state of amyloid that traps free floating "harmfull" amyloid into a dense core where it cant do any harm.
The harmfull effects of amyloid are being shown to be mediated by the soluble and oligomeric species - that is a single amyloid peptide or a bunch stuck together, usually with a mass of less than 100kda. So far we dont know if immunotherapy in humans will affect these harmful "amyloids" or not. The post mortem results from the Elan trials were pesimestic at best - patients who recieved the injections had reduced amyloid plaque burden, but cognitively, at best (and this is from the company line) did not cognitively deteriate as fast as without the antibodies.
Either way I'll put my money on a nice BACE inhibitor. Forget about the gamma-secretase ones, thats one complex you really dont want to be messing with!
siRNA is the way forward - the big deal here is not the possible cure for cancer, but a delivery route for the RNAi into cells. siRNA is the future of pharmacolology, a specific knockdown of enzymes and proteins without non-specifically inhibiting similar enzymes. The problem with siRNA, which we use very effectively in cell cultures by transfection techniques, is getting the large RNA molecules accross the fatty cell membrane and into the cell where is can do its work.
Previously people have shown that tail vein injections of siRNAs could cause knockdown of proteins in the liver, as the siRNAs accumulate there, but since we have been striving for a more effecient route into cells, especially in the CNS. Ironically we have been using a similar technique - by complexing siRNA to cholesterol and then further complexing with cyclodextrin to get the whole molecule into neurons, but that approach failed for us. We had considered using a receptor (as this group has used transferrin), such as muscarinic receptors but hadn't gone further.
The other approach which is having good success at the moment are using thiol conjugated siRNAs and attaching a further molecule called "penetrance". This effectively allows the siRNA to pass the plasma membrane.
Regardless these leaps in siRNA deliverance will revolutionise medicine over the next 20 years.
Slashdot Mirror
First off it was obvious from the Elan trials that suddenly making a protein abundant in plaques in the brain (amyloid beta) into an antigen would lead to inflammation.... what were they thinking!
Immunotherapy has been successfully used in multiple mouse models of AD, including peripheral active and passive immuunisation. But here is the question: Is removing extracellular amyloid plaques in human AD going to cure the disease?? The probable answer is no, more and more researchers are showing that plaques are an end point - a protective state of amyloid that traps free floating "harmfull" amyloid into a dense core where it cant do any harm.
The harmfull effects of amyloid are being shown to be mediated by the soluble and oligomeric species - that is a single amyloid peptide or a bunch stuck together, usually with a mass of less than 100kda. So far we dont know if immunotherapy in humans will affect these harmful "amyloids" or not. The post mortem results from the Elan trials were pesimestic at best - patients who recieved the injections had reduced amyloid plaque burden, but cognitively, at best (and this is from the company line) did not cognitively deteriate as fast as without the antibodies.
Either way I'll put my money on a nice BACE inhibitor. Forget about the gamma-secretase ones, thats one complex you really dont want to be messing with!
siRNA is the way forward - the big deal here is not the possible cure for cancer, but a delivery route for the RNAi into cells. siRNA is the future of pharmacolology, a specific knockdown of enzymes and proteins without non-specifically inhibiting similar enzymes. The problem with siRNA, which we use very effectively in cell cultures by transfection techniques, is getting the large RNA molecules accross the fatty cell membrane and into the cell where is can do its work.
Previously people have shown that tail vein injections of siRNAs could cause knockdown of proteins in the liver, as the siRNAs accumulate there, but since we have been striving for a more effecient route into cells, especially in the CNS. Ironically we have been using a similar technique - by complexing siRNA to cholesterol and then further complexing with cyclodextrin to get the whole molecule into neurons, but that approach failed for us. We had considered using a receptor (as this group has used transferrin), such as muscarinic receptors but hadn't gone further.
The other approach which is having good success at the moment are using thiol conjugated siRNAs and attaching a further molecule called "penetrance". This effectively allows the siRNA to pass the plasma membrane.
Regardless these leaps in siRNA deliverance will revolutionise medicine over the next 20 years.