It is a staggering number when you look at the effect of immunotherapy, despite its beneficial effect, that has led to 41% ARIA in Alzheimer’s disease patients. Most of it is detected through imaging modalities. To my knowledge so far, nobody has undertaken research to try to understand the molecular mechanism underlying ARIA.
We were interested in the context initially of prion disease when we discovered that cross-linking PrPSc, the cellular prion protein, led to disturbances mainly related to allergy in the context of using a mouse model of prion...
It is a staggering number when you look at the effect of immunotherapy, despite its beneficial effect, that has led to 41% ARIA in Alzheimer’s disease patients. Most of it is detected through imaging modalities. To my knowledge so far, nobody has undertaken research to try to understand the molecular mechanism underlying ARIA.
We were interested in the context initially of prion disease when we discovered that cross-linking PrPSc, the cellular prion protein, led to disturbances mainly related to allergy in the context of using a mouse model of prion. We saw an ARIA-like behavior when using infusion of this immunotherapeutic antibody into the brain. So from that we reasoned that probably similar events might have occurred in Alzheimer’s patients. But we also see that in Alzheimer’s disease animal models, mainly mouse models. So from that point we use similar antibodies used by large companies in the context of treating Alzheimer’s patients in clinical trials. And to our surprise, what we discovered is that these antibodies led to mainly immunological disturbances related to allergy, more specifically type I hypersensitivity. But also, it was intriguing for us to see that, and this is in the context of using stem cells and other cell lines, there was a clear shift from an anti-inflammatory to a pro-inflammatory cytokine profile and that was exacerbated if microglia were added into the mix.
We have some studies currently being undertaken in mouse models. To cut the story short, what we’ve discovered is that this type I hypersensitive pathway is not related to histamine, so it’s a histamine-independent pathway. We are looking into two different specific pathways.
I think our study does highlight the importance of including that sort of characterization and screening regimen part of these trials. We do believe it’s important to select those immunotherapeutic antibodies by adding an extra layer, looking specifically on whether these antibodies might be involved in causing toxicity, but more specifically type I hypersensitivity and the assays are well established to do that. So this is not really taxing to medical research institutes and companies to be able to add that extra step, an extra layer into the characterization process.
