Albers’ Clinic and getting us in. Need to send emails.
AD symposium, September, main campus. On clinical research and lab research.
His research: mice noses and AD. Mice olfactory neural system well studied, is a good test bed for treatments (but of course, not for us). Smell memory as an early, noninvasive screening for AD.
AD might be a syndrome, not a disease with many different mechanisms leading to the final phenotype. Can start at different parts of the brain and then spread, with different initial symptoms that progress to the well known characteristics. Example, disease starting in the back: woman could see but not recognize letters until she traced them out with her fingers. Connection between vision and language severed. Disease starting at the front: depression starting late in life (actual depression, as opposed to AD depression, starts much earlier in life). Patients could have problems in an area of the brain called Insight, which tells them if something is wrong with them, so they end up feeling fine. Often the caregivers have the hardest time dealing with the disease.
How would early detections help if we don’t have real treatments? All clinical trials that target the disease at the later stage have failed. But the idea is that it would work if the drugs had been introduced earlier at the asymptomatic stage (remember, disease starts 10-15 years before symptoms!)
Clinical trial started very recently: A4, under Reisa Sperling. Uses antibody against AB in people who are asymptomatic or have small memory problems, but have AB in the brain, shown PET scans (How did they choose the people?). Antibody didn’t work in older patients, will try to see if it works in younger ones.
Delivery:
AAV9 as a potential vector, but very small capacity, 5.4kb.
Roger Rosenberg. Injected DNA into the blood and got it into the brain.
Intrathecal injection. More invasive.
If treatment works, the delivery is a whole project of its own.
How people would react to the use of virus in general is issue. But now there is a clinical trial. And as people become more educated, and successful trials, that can change. In AD the concerns with viruses are mitigated because of the large patient population (I’m not sure how)
Specificity of delivery: use molecular biology to help, brain specific promoters. With intrathecal injection, less will get into the blood stream.
Micoglia:
If we engineer microglia and then introduce it into the brain, it would address the issue of specificity, but there is indication that microglia are involved in the problem itself.
Brain is an immune privileged organ. It uses immune system genes to protect itself. Introducing immune cells in the brain could have unintended consequences, eg, if microglia migrate to where they are not supposed to be, etc. But it’s a hot topic; worth exploring and being explored.
Failsafe:
If treatment is not doing anything or causing harm, there needs to be a way to stop it. For example, if using virus, build in a way to kill the virus. Give a certain drug to kill the virus. Not well designed trial 10 years ago: stem cell trial in Parkinson’s disease to get dopamine levels up. There was too much dopamine so, too much movement. Patients would prefer their Parkinson’s to more movement.
Biomarkers:
Ongoing research to find biomarkers to show that AD is being treated, at a smaller time scale. However, there is no consensus about which biomarkers to use. (Relevant to us because judges might ask how we would test if our circuit is working in humans…)
Shinjini’s comments/epiphany: Since we are planning to detect and treat AD in younger patients who are asymptomatic/don’t actually have the disease, they would not agree to have things injected to their brains. So, I go against injecting microglia and for viral/other noninvasive delivery mechanisms.