Dr. Peter T. Lansbury, Jr., Ph.D. serves as Chief Scientific Officer at Lysosomal Therapeutics Inc. He is also Professor of Neurology at Harvard Medical School and he has served as Director of the Brigham and Women’s Hospital Morris K. Udall Center of Excellence in Parkinson’s Disease Research as well as chair of the Harvard Laboratory for Drug Discovery. For the past thirty years, Dr. Lansbury has studied the biochemical processes underlying Alzheimer’s disease, Parkinson’s disease, prion disease, and ALS, with the goal of translating this knowledge into novel medicines.
(Lysosomal Therapeutics was founded by Dr Joseph Mazzulli and Prof Dimitri Krainc (Northwestern University) in 2011. The company is focused on discovering and developing compounds that will increase the activation of the glucocerebrosidase(GBA) enzyme. Currently they are focused on Parkinson’s, for which they are developing a drug called LTI-291. Preclinical studies have shown that LTI-291 easily crosses the blood-brain-barrier and accesses the glucocerebrosidase enzyme within the brain. Lysosomal Therapeutics have partnered with the Irish Pharmaceutical company Allergan to take LTI-291 into clinical trials (Click here to see the press release). – From the Science of Parkinson’s website
The following has been paraphrased from an interview with Dr. Peter Lansbury on January 29, 2018.
(Click here for the full audio version)
How much is known about what the GBA enzyme actually does?
Well, the amount known is increasing, but the “known unknowns” are increasing at a faster rate. The more we learn about it, the more we discover other things that it could be doing. Our therapeutic strategy is focused on the known functions, but there could be functions that are not known that are responsible for Parkinson’s risk and progression that everybody is missing. I’ve been working on neurodegeneration for a long time now and what people do is they look at a mutation and its effects in a test tube, with a hypothesis in mind about what the protein it produces should be doing. Though you can’t love your hypothesis too much, at the end of the day you do have to make decisions. We think that if you increase the enzyme activity in GBA carriers it could have a therapeutic effect. So all we can do is make a molecule that is very safe, that’s well tolerated, that gets into the brain, and that increases the activity of the enzyme. Once we’ve done that then we have to run a human trial and until that is done you never really know for sure if what you are testing is going to work.
Do we have any clues as to what factors might account for the incomplete penetrance of the gene? (In other words, why do some people with the GBA mutations get Parkinson’s disease but most don’t?)
If you believe it is the lower activity of the enzyme that is causing this disease, then there are many factors that could be causing that lowered activity. For example, the pH dependence of the enzyme is very steep. So if you have a genetic makeup that results in your lysosomes being incompletely acidified, that is going to change the penetrance of the mutation. But still there is nothing proven that changes the penetrance, though there are large scale genetic studies starting to look at those modifying factors.
How much does the compound that Lysosomal Therapeutics uses, LTI-291, increase GCase activity? (GCase is short for the enzyme that the GBA gene produces)
It depends on the dose, but our target has been to increase activity by about 30%, which we believe is sufficient in many GBA carriers to get their lysosomes to start functioning properly. However that is also dependent upon being able to safely get the compound into the brain. It is a dose-dependent activation and the ongoing clinical trials will help us establish the optimal dose.
What stage are the trials at?
We are still in early phase 1, which is a healthy control trial where we are looking at a single dose of the drug in healthy elderly volunteers. Then we will look at ascending dose increments. We are also recruiting to test this on people with GBA-PD and will do one month of dosing in those patients. These will just be looking at safety and tolerance issues. Then we’ll be able to look at biomarkers to see the effect that the drug is having in the brain. If it has the effect that we predicted, at a safe and tolerable dose, then it is time for a one or one-and-a-half year clinical phase 1 study. Unfortunately, with this disease, it is still very hard to measure the efficacy of a proposed therapy because it progresses so slowly. I believe that the only way to do so is once you have proven the drug is safe you should then move to a phase 1 study that follows people with the disease for at least one year.
There are a number of strategies being tried to target this mutation by other companies (Sanofi-Genzyme, Ambroxyl, Voyager Therapeutics, etc. ), what advantages or disadvantages do you suspect the compound that Lysosomal Therapeutics is testing will have compared to those other ones?
I don’t know exactly what others are doing but I think the gene therapy approaches are very attractive (using viruses to transplant normal genes in place of mutated ones). But there are thousands of small molecule drugs on the market that do cross the blood-brain-barrier (BBB) and are safe. People say the BBB makes small molecule options difficult, but if you have the right people in place that know how to get drugs across then you can overcome the BBB. Another strategy being talked about is to get enzyme replacement into the brain. These strategies that involve stimulating protein production in the brain are challenging because it is very difficult to get them into targeted areas of the brain. So I like the small molecule approach that we have been working on for years.