Casey Lynch: Targeting Pathogens to Treat the Brain

Casey Lynch: Targeting Pathogens to Treat the Brain

Lynch: Good morning everyone. How many of you have loved ones with Alzheimer’s or have had Alzheimer’s? At least half. How many of you are scared of getting Alzheimer’s? Not everyone? I certainly am. To set the stage for our work in the next five minutes I’d like to convince you that a cure for Alzheimer’s is within reach.
To set the stage I’d like to tell you about an Australian researcher and physician named Barry Marshall. In 1982 he discovered along with his colleague Robin Warren that the bacteria H. pylori could be cultured from and was the likely cause of ulcers. This was met with extreme skepticism from the establishment because everybody knew that ulcers were caused by spicy food and stress. In 1984 he went so far as to drink a culture of the bacteria in order to prove his case and eventually in 2005 the pair was awarded a Nobel Prize for the discovery and ulcers are now treated with antibiotics.
This is Dr. Stephen Dominy. He’s a UCSF psychiatrist with an interest in infectious causes of neurological disorders with HIV-dementia being a case in point. In June 2013 I got a call from Steve saying that he had evidence of an infectious cause of Alzheimer’s. My name’s Casey Lynch I’m an entrepreneur with a background in Alzheimer’s research and like many in the field I’ve been frustrated with the single-minded focus on amyloid beta as a target. So I was very intrigued. This is what Steve showed me. Across the top what you’re seeing is increasing magnifications of an Alzheimer’s brain, Alzheimer’s brain tissue and across the bottom is healthy tissue, healthy brain tissue from the hippocampus. The brown staining there is a bacterial protease, a toxic bacterial protease filling up these neurons. On the upper right side what you see is a blood vessel with a concentration gradient moving away from that vessel indicating a potential point of entry through the blood brain barrier. So this is very exciting, very intriguing but we all know the difference between correlation and causation. So Steve and I laid out a plan to convince first ourselves and then the rest of the community that this is not only credible but there is a direct path to treatment. I did not ask him to drink the bacteria but we did some other things.
First of all, we looked at every Alzheimer’s brain we could get our hands on, 43 so far, 100% of them are positive for this bacterial protease. We also looked at pre-clinical cases so people with pathology but no symptoms yet. One hundred percent of those 30 brains are also positive. Finally, also, healthy brains of course and in fact some of the healthy brains are also positive. So this is exactly what you would expect for a disease-causing event factor. First, it infiltrates healthy brains then it triggers pathology and eventually you lose enough neurons to get symptoms. You can lose a lot of neurons before you start to show symptoms so that part, that story fits. The second thing we did is we infected mice. So this how you can prove causation. We did a peripheral infection in two mice and two other labs have also done this now and what you see after that, you see brain infiltration of the bacteria, you see neurodegeneration, cognitive dysfunction, inflammation, complement cascade activation and also amyloid beta induction. So this is a sticky protein that’s in the popular press all the time as the definitive cause of Alzheimer’s and we’re triggering it by this infection. We’re triggering brain amyloid in regular old mice. These aren’t transgenic mice of any sort, so just like humans. So what’s going on here? Well, there’s actually evidence that this amyloid protein that everyone’s been focused on may be an antimicrobial peptide. So humans make these peptides in response to infection. It’s part of the innate immune system. They form oligomers and in the presence of bacterial membranes they form pores that let calcium in and kill the bacteria. They can also kill host cells but they have preference for bacterial membranes and the literature supports the idea that amyloid beta is killing bacteria and are data supports the idea that it’s triggered and is a marker of this infection rather than necessarily the cause of Alzheimer’s. Over 10 clinical studies now, trying to target amyloid have failed. Whenever we get into the big studies, Alzheimer’s is extremely variable so you really need a huge study to know if something’s working. So far we believe this is a marker of the infection. So to summarize we think that a very common peripheral infection of a bacterial pathogen gets into the brain of some people. So aging increases the leakiness of the blood brain barrier, genetic risk would increase this effect. So you may have all heard of ApoE4 as a genetic risk factor that predisposes people to Alzheimer’s. When you put this gene into mice they get a leaky blood brain barrier so we think those people are more susceptible. Trauma, these football players and boxers who are having head trauma and ending up with dementia perhaps this is letting the bacteria in. And finally, the bacteria alone, so we think the pathogen is the primary contributor to the neurodegeneration but it’s also triggering these other bystanders, which may also be contributing as well, but if we can intercede at the point, at the early point, at the brain infiltration or blocking the bacterial pathogenic effect we can stop all of these things.
So Cortexyme has been working on bacterial protease inhibitors to treat Alzheimer’s disease. This slide shows neurons in a dish, on the right regular neurons in a dish, in the presence of the bacterial protease they die. In the presence of our protective compounds they can be rescued and they can also rescue the beta amyloid pathology as well. Cortexyme is based in south San Francisco, we’re at the Johnson & Johnson Innovation Center, we’ve been funded today by Breakout Labs, Dolby Family Ventures and angels. We’re excited that these groups are ready to get out of the box and fund new ways to cure. We are working on  a new round of financing to reach human clinical studies in the next three years.


Casey Lynch

Co-founder and CEO, Cortexyme

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