Gene Therapy for Alzheimer and Neurogenerative Disease

Ronald G. Crystal, MD

This fall at the Alzheimer’s Drug Discovery Foundation (ADDF) International Conference, Ronald G. Crystal, MD, presented to more than 800 attendees on the current state of gene therapy for APOE4 influenced Alzheimer disease and other neurodegenerative disorders, detailing ongoing development and the current state of a small trial in patients with Alzheimer.

Crystal, who is the chairman of the Department of Genetic Medicine at Weill Cornell Medicine, urged attendees to watch this therapeutic development closely, noting that the progress of gene therapy after decades of research reveals a promising future. With regard to Alzheimer, the plan is to provide the APOE2 gene—which literature has suggested may offer a protective effect against Alzheimer disease—to individuals who are APOE4 heterozygotes.

In an interview with NeurologyLive, Crystal spoke to the takeaways for the clinical community and discussed the current state of that research. He also explained some of the challenges of developing these therapies, specifically as it relates to the differences in approach to intracellular versus extracellular targets.

NeurologyLive: What are your thoughts are on the current state of gene therapy development?

Ronald Crystal, MD: If you take the common neurodegenerative diseases and make a list of them, they have certain things in common despite the fact that they're very different diseases. One of the things that they have in common is that they are chronic diseases, right? They also, obviously, are in the nervous system and they have a therapeutic challenge—the blood-brain barrier. Those are 2 things that are key things that gene therapy can do. You can use gene therapy to have genes put directly into the nervous system, that bypasses the blood-brain barrier problem. Also, with gene therapy—if it works and if it's safe—there's a single administration to cure it forever. That's why so many people are interested, like us and many others.

We’re interested in gene therapy for the central nervous system. Now the issue is what's the state of the art and where are we? It started with us and some others approaching some diffuse diseases, like the lysosomal storage diseases, by taking the affected individuals to the operating room, putting Burr holes in the skull, catheters directly into the brain, and infusing the viruses that we use to carry the gene. But then the investigators start thinking, could you do this intravenously? That would obviously be a lot easier, right? Spinal muscular atrophy (SMA) was a good example of that. But the problem there was that even though it worked and it’s an approved therapy, is that it’s in infants before the blood-brain barrier is fully formed. With the blood-brain barrier fully formed, it's much tougher to use intravenous approaches because you think about how do the viruses get across the blood-brain barrier?

We and many others then started thinking about other strategies to deliver viruses to the brain. One approach was intraventricular: put a burr hole in the skull and a catheter directly into the cerebral spinal fluid in the ventricle. That's one approach. Then we started thinking about using intracisternal or intrathecal approaches, as well. That's evolving more as the favorite approach. Now, that doesn't mean it solves everything. But there's a lot of data in the field by many investigators, including us, that using intracisternal—or perhaps going down a little lower to C1, C2, or going down even lower and threading a catheter up—is another way to do it. If you can do that without toxicity, although there are some issues, you can get widespread expression throughout the brain. So that's been a part of a revolution in gene therapy for the CNS.

With regard to the viruses that are used, we think of those gene therapy terms as serotypes, and what is being used in the field is adeno-associated viruses (AAVs). There are some that are derived from humans, and some that are derived from nonhuman primates, and then there are some that are man-made in the laboratory by taking known ones and modifying the capsid. That’s done by sort of evolutionary techniques or directed techniques where you make specific changes. In the field, people are developing more capsids that may be a little better here and there, but I think in general, we have the capsids right. The strategy now is to use those capsids to choose the gene of interest and then the approach in terms of how we're going to deliver it.

Gene therapy for the CNS has really evolved over the last decade or so, and I think it's now at the point where there is obviously is an approved drug now, and I think you're going to see a number of approved drugs.

For neurodegenerative disease specifically, what are the challenges and what work are you and your colleagues doing?

In terms of the neurodegenerative diseases, the issues are with the hereditary disorders and the nonhereditary disorders and then sort of in-between disorders. The hereditary disorders like the lysosomal storage diseases, or the genetic form of ALS, or frontal temporal dementia, or Parkinson, or Huntington—you know what the target is. There becomes a delivery problem, a safety problem, an efficacy problem because you know you can deliver the gene, but can you accomplish it and do it sufficiently?

Then there's a group of disorders like we're interested in like Alzheimer, where we're taking advantage of the epidemiology that the apolipoprotein (APOE) gene comes in 3 flavors—APOE3, APOE4, and APOE2. Now, 85% of us are APOE3, but then if you're an APOE4 homozygote, you have a 15- to 20-fold increased risk for the development of Alzheimer, and if you develop it, it's more aggressive and occurs earlier as well. But if you're lucky enough to inherit from your parents APOE2, you have a decreased risk of Alzheimer, and if you do develop Alzheimer, it's milder and occurs later.

What got us interested in it was the heterozygotes. If you're an APOE2-APOE4 heterozygote, the APOE2 takes away most of the risk—not entirely—for APOE4. APOE is made mostly by glia and astroglia, and the receptors are mostly on neurons. The particles are formed in the extracellular space. So, if you're heterozygote, your extracellular particles are APOE2-APOE4 heterozygotes. Our whole strategy is to bathe the brain of APOE4 homozygotes in APOE2, so that the particles become heterozygote or even more APOE2. What we're doing is ignoring the pathogenesis of the disease, whether it's its amyloid, phospho-tau, inflammation, or multiple other mechanisms, all of which are being studied. We're proximal to that because we know that APOE4 and APOE2 affect multiple sites in the pathogenesis. That's the whole strategy. The way we're administering it is that we decided not to go intracisternal, we do it at C1 or C2. There is a sort of argument in the field about what's best. As you probably know, there are some blood vessels that run at the roof of the cisterna magna, so there's a little bit of a risk to going into the cisterna magna, so we decided to do C1 or C2, just below that. It's done under CT scanning, it's an outpatient procedure, and it takes about 25 to 30 minutes to place the needle, and about 5 minutes to administer. So far, we've treated 3 patients and we're looking for more, and we are actively following them.

What’s the takeaway for the clinical community from your perspective?

Gene therapy is essentially a drug delivery system. It's not an end-all, but it's a drug delivery system, just like small molecules are and monoclonal antibodies are. Gene therapy is real now. We and others have been working on it for several decades now. We now have approval for 1 drug in the field, and I think that one of the real challenges in neurodegenerative disease is the blood-brain barrier and that we can overcome that with the technology that we have. The questions are: can we do it safely, can we get enough in, and can we design the right targets?

What I'd want people to take away is to pay attention to the space. This is going to be something real, and there'll be select diseases where this will be a therapy that over the next decade will become real for you in terms of treating patients.

Transcript edited for clarity.