HD Insights Q&A.
HD Insights interviewed Dr. Paul Larson, professor and Vice Chair of Neurological Surgery at the University of California San Francisco, Chief of Neurosurgery at the San Francisco VA Medical Center and Surgical Director of the Parkinson’s Disease Research, Education and Clinical Center. Larson is widely viewed as a preeminent global expert on/primary investigator in clinical trials of vector-delivered medications. We asked Dr. Larson for his insights on the current state of AAV vector delivery, trial participation and how our current knowledge translates to HD applications.
Dr. Larson, how did you become involved in adeno-assisted viral vector (AAV) research?
Here at UCSF, our involvement stems from two different beginnings. One is an AAV gene therapy program that started here in San Francisco. A scientist had done all the basic science research, and when his preclinical work got to the point where it could be translated into clinical trial, he turned to us, as Parkinson’s surgeons working at the same institution, to take the next step.
The second thing that helped launch our trial work was, literally, a cold call from a company saying, “We have done preclinical work, and we’re ready to do a clinical trial.
We know you do a lot of Parkinson’s surgery and hey, will you help us out with this study?” We looked at the science behind that particular therapeutic delivered with AAV, and it looked sound and reasonable, so we started to partner with them.
What is it you are trying to accomplish on a microbiological level by injecting AAV vector in the brain of a Parkinson’s patient? How does this theoretically work for the
Gene therapy, if you think about it very basically, is using a virus as a safe carrier to get instructions into the brain cells to have them change their function in a beneficial way.
The vector is like an Uber, carrying a gene that we have put in that virus. The virus latches onto brain cells and releases the gene, which then programs the cell to do something different.
In Parkinson’s, there is an enzyme, amino acid decarboxylase, that helps people make their own dopamine and also converts medications that they take into dopamine. Since the levels of dopamine are falling as the disease progresses in Parkinson’s patients, what we are doing is putting in a gene that gives the instructions to the cell to make that enzyme. We are teaching the brain cell to produce more of that enzyme.
In Huntington disease, the problem lies in the production of an abnormal protein, the huntingtin protein. With HD, we are going to try to block production of that abnormal protein by delivering instructions for the brain cells to make a little fragment of RNA that will latch onto the abnormal RNA responsible for making the huntingtin protein.
Would you give us a little history on your Parkinson’s trials involving AAV delivery? What has changed and what are the most important things you have learned over the 20 years you have been conducting them?
MRI-guided technology provided a crucial learning opportunity that enabled us to deliver these AAV-based therapies more effectively, and that has made a huge difference. As recently as five to seven years ago, Parkinson’s gene therapy trials were done using traditional stereotactical surgical techniques. This involves placing a head frame on the patient, using an aiming device to place a cannula into the brain, and then performing a blind infusion of a certain volume at a certain rate.
Since we couldn’t visualize these infusions, we had to rely on the assumption that our infusions were leading to a nice spherical distribution of virus, easily covering the area of the brain we wanted to treat. We now know that that is a very naïve notion, that when you put a cannula in the brain and infuse fluid, it does not behave in a predictable way. It can leak up along the cannula, it can leak out along the little perivascular spaces around the blood vessels, and it generally misbehaves.
Many of the phase II Parkinson’s trials ended up being negative — no clear evidence of benefit — even though the phase I results looked very promising. There may be several reasons for those failures, but I think a large part of it was these incorrect assumptions about how fluid infusions behave in the brain.
Now, intraoperative MRI provides a solution to the problem, and we’ve used it in our last three Parkinson’s trials. We co-infuse the virus with a contrast agent, and watch the infusion as it
is delivered into the brain. If it’s leaking up the cannula or if it’s leaking out of the target area, being carried away from the target by the perivascular spaces, you see it happening in real time. Basic science work tells us that if we are using AAV, where the contrast is going, the virus is going, for the most part.
I think that certainly when we infuse AAV vector from this point forward, MRI-guided delivery is absolutely the way to go. We aren’t unique in this — it has become, for many neurosurgery applications, the technique of choice.
How do you expect control of the distribution will influence trial outcomes?
When you can see what’s happening, it’s really very helpful. Seeing that we had leakage of vector away from the target and that we were nowhere near covering the intended area of the target (the putamen in these trials) with the volumes we were infusing was a game-changer for us.
In the early Parkinson’s trials, we were using 40 to 100 microliters of vector in a certain concentration. Now we know that those are very, very small volumes. Our mathematical modeling had told us were going to reach about 50 percent of the putamen, but we were really reaching about 15 percent. So, it was no wonder these trials did not show an obvious treatment effect; we were were probably being way too conservative in terms of the volume of vector we were delivering.
Now we know we can use much higher volumes safely. For example, in one trial we are currently doing, we’re using up to 1800 microliters, so we’re talking orders of magnitude more vector than we were using before. In Parkinson’s, as we’ve used more vector and gotten better coverage, clinical outcomes appear to get better. Objective markers of enzyme activity like PET imaging are looking better.
The only caveat is that, so far, we only have information from open label trials, which are subject to a strong placebo effect in Parkinson’s disease. The phase II trial we are currently running is going to tell us if the robustness of this technique is really going to stand up to the rigors of a double-blind trial.
It seems like these intraoperative MRI procedures are not ubiquitous, and potentially there is a lot of learning in doing this. Do you see it changing the way neurosurgery is practiced in the U.S.?
There are 50 to 60 centers around the U.S. that are currently doing MRI-guided neurosurgery to guide placement of stimulating electrodes into the brain or laser fibers that treat things like epilepsy. Most of these procedures are done on regular, standard MRI scanners that are actually located in radiology. Any medical center that has an MRI and a functional neurosurgeon can potentially do it.
I think that the landscape of neurosurgery is going to change and I think we will be doing more therapeutic delivery to the brain for a variety of treatments, whether it is delivering gene therapy, stem cells or chemotherapy medications. MRI-guided delivery will be the technique of choice for many of these therapeutic agents.
In two recent phase I trials, we used the same intraoperative MRI technique, though using a slightly different approach.
Instead of coming through the frontal lobe to get to the target, we came through the parietal-occipital area, and that allowed us to use higher volumes at a single pass. We’re currently in a multicenter phase II Parkinson’s study using that same technique. We have brain tumor surgeons here at UCSF that use
MRI-guided delivery to do gene therapy for patients that have recurrent brain tumors. They’ve already been treated with surgeries to resect the tumors, but they recur. They are using gene therapy to make the recurrent brain tumor cells susceptible to a drug that you can then give the patient systemically. You can potentially change the biology of a tumor by making it vulnerable to a drug that it wasn’t susceptible to before.
In HD, it’s happening, in Parkinson’s, obviously, it’s happening. There are people looking at gene therapy trials in Alzheimer disease. I think it is going to be an interesting decade ahead.
What are the challenges in AAV infusions into a brain with greater atrophy, as brains of people with advanced HD have?
HD is definitely a different disease from Parkinson’s. The atrophy that occurs in HD poses challenges for infusion. The folds in the surface of the brain get deeper and the ventricles (fluid spaces in the brain) get larger, so the corridors for safe passage of an infusion cannula become narrower. In addition, the structures that you are trying to infuse are also atrophying. So there definitely will be challenges moving forward, but I think we can overcome them.
Some of the groups we’ve talked to express concern about being in a study where they may have sham surgery. Any advice on how to handle that in the context of a trial?
This is probably the most common concern that potential participants raise when you talk to them about being in a trial like this. We really take time to explain the need to do a placebo-controlled study, and that there is a placebo effect with almost any intervention you do. If you look at the history of Parkinson’s disease, which is the neurodegenerative disease where the most study trials have been done by far, you see a very strong placebo effect of between 30 and 40 percent improvement that can persist for 18 months or longer. So, we tell patients, “Look we have a therapy, we think it’s promising, but the only way that therapy has a chance of becoming a standard treatment for you, and for the millions of other patients like you, is in the context of a placebo trial.”
We really ask our participants to be partners in the science with us. The patients that have a placebo intervention are as or even more important than the people getting the study intervention.
In many trials the sponsor will generally say, “If this trial is positive and it looks like it’s safe and it looks like it works, we will give you the study intervention once the trial is done.” However, the study sponsor might think it’s safe and the FDA might not agree, so there are no promises.
We also point out that we’re doing this trial because we aren’t 100 percent sure it works, and there may be safety concerns that arise when we do it in a larger number of patients. I think it’s human nature to have a buy-in, to want the treatment. We tell people to think about it from both sides… you may not want the real treatment if it ends up not really working. There were several stem cell trials for Parkinson’s in the 90s, and even though the phase I studies looked good, the patients that got the transplants didn’t get better, and some of them developed a really significant complication of frequent involuntary movements. So there have been trials in the past where you didn’t want to be in the active treatment group.
So those are some of the issues we talk through with all our participants. No matter how gung-ho they are, we have those discussions with them.
Everyone has their own self-interest that they want to get better, but if you talk about people who sign up for these trials, almost without fail, they’ll tell you, they really want to do something for the greater community: “I have this disease and of course I want to get better but I also want to push the science forward in helping people who are suffering like me and who maybe aren’t ready or are nervous about doing something like this.” If it weren’t for patients really stepping up and saying “Look, I’m willing to do this,” even if they don’t know what they are going to get, we’d be nowhere near where we are today. It’s a tremendous contribution they are making. And most of the patients are very aware of that.
One of the things we are noticing with these trials is that there is a really strong team all the way from the coordinator to the neurologist to the neurosurgeon. Can you give some advice to neurologists that want to do this about how to prepare to treat patients and interact effectively within a neurosurgery team?
So far, these procedures have only been done in the context of a clinical trial. You have to believe in what is being studied and be excited about it. You have to be comfortable talking to patients about the therapy, and be willing to spend the extra time it takes to do that. Finally, you have to enjoy working in a team, as this is very much a team effort.
I’m very close with my neurology colleagues. In fact, I am in the same physical space as my neurology partners. When we see a new patient who is referred for potential treatment, the neurologist usually sees them first I see them immediately afterwards. Sometimes, we will actually even see them at the same time.
I can’t overemphasize how important the study coordinators are. These trials are very complex, with number of assessments that are done, the coordination that requires, the regulatory burden that exists, the volume of study records that are generated and maintained, the IRB approvals. It really is a three-headed beast — it’s the neurologist, the neurosurgeon and the study coordinator. I would argue in many cases that the study coordinator is the most important person in the context of these clinical trials. So the team approach is really mandatory. It’s the only way you can be successful in doing something like this.
Looking back on all the work you have done, any top things you wish you had known when you started this journey?
Certainly we now know that the surgical techniques we were using in the beginning were not sophisticated enough. WhenI look back at trials that we started in the early 2000s, we just didn’t know any better. Part of the learning has just been a simple evolution of science and surgical technique. We were using what we thought were the best techniques at the time.
One overarching message I would pass on is to stay flexible. Most neurosurgeons can relate to this example. I did my putaminal infusions from a trans-frontal approach for over a decade because it was considered “standard,” but it was clearly not that efficient. My partner suggested that we place the infusion cannula in the putamen from a posterior approach to minimize the number of brain penetrations and increase efficiency of the infusion. I was very resistant at first, but ultimately he showed me that it really was safe and effective. The lesson here is to keep your eyes and mind open to what’s going on, and know that you will need to adapt over time.