Holistic Approaches to Treating Parkinson Disease May Be More Effective

Paul Y. Song, MD
Credit: NKGen

Currently, many treatments for Parkinson disease (PD) are simply aimed at ameliorating certain symptoms of the disease. As the complex neurological disorder becomes more well-understood, however, it may behoove researchers to begin trying to tackle the root causes of PD.

NKGen Biotech is currently evaluating SNK01, an autologous natural killer (NK) cell therapy, for PD, with the intention of simultaneously reducing build-up of α-synuclein in the brain and reducing neuroinflammation, both of which have been linked to PD disease manifestation. CGTLive® recently spoke to Paul Y. Song, MD, the chairman and chief executive officer of NKGen, to learn more about the company’s rationale behind the approach, which it is also evaluating for Alzheimer disease (AD).

CGTLive: Can you discuss the current landscape of care for PD and the unmet needs that remain for this patient population?

Paul Y. Song, MD: Right now, most of the focus in the treatment of PD has really been focused on treating the symptoms rather than trying to get to the root cause. Whether it be helping to deal with resting tremors or some ability for patients to have better control of their overall neurological function, it still does not address what is causing the original deficits and problems that these patients are having. What's emerging is that there are 2 elements to PD. One is that there's a protein that seems to accumulate in the brains of patients called α-synuclein proteins—very much like amyloid proteins being implicated in AD. A lot of attention has been placed on ways to try to remove the proteins, very much so with antibodies that are directed at this. You have companies that are focused on this and doing clinical trials with such an approach.

Why is NKGen seeking to use NK cell therapy to treat PD?

What we found through our work in AD patients is that when we took patients’ own NK cells and enhanced them, made them much stronger, and drew out the activating receptor expression, and gave them back to patients via simple intravenous injection, that they were able to cross the blood-brain barrier and not only reduce amyloid proteins in AD patients, but we saw reductions in tau proteins and α-synuclein proteins [in these patients], as well. Based on the reduction of all of these proteins, and specifically α-synuclein proteins, we felt that there could be some potential for its use in PD. Now, while a lot of the attention has been focused just on the proteins, what has now been clear in many neurodegenerative diseases is there's a strong neuroinflammation that has happened, and it's almost an autoimmune phenomenon. What I mean by that is whether or not the proteins are amyloid proteins, as in an AD model, or α-synuclein proteins, or even tau proteins, that T-cells become activated and—in much the same way as when T-cells go awry and attack your body in autoimmune diseases—these T-cells cross into the brain and in their attempt to try to clear the proteins end up causing a lot of collateral damage. T-cells unfortunately have only 1 receptor, so their ability to discern normal healthy tissue from diseased tissue sometimes is not great and there can be a lot of collateral damage. So what you're finding is if you just remove the protein, but leave the inflammation and damage behind—this is one of the reasons why people believe that you're not seeing any real profound improvement in amyloid-targeted therapies in AD. In much the same way, I think for PD this could also be an issue if you just remove the α-synuclein protein, but leave the inflammation and damage behind. One thing we're finding also—and this is not our studies, but in general the medical community’s—is when they follow patients who have been diagnosed with PD that over the course of time you do see this transformation in their immune cell signature. Specifically, you start to see more of these autoreactive CD4 and CD8 T-cells that are both in circulation as well as in the cerebrospinal fluid (CSF). The second part that we have been pleased to find out is that NK cells actually have a mechanism to identify and eliminate these autoreactive T-cells. Much of the work has come from other researchers looking at immune profiling in autoimmune diseases. What they found is that through 2 receptors, primarily NKG2D and DNAM-1, NK cells can identify these circulating T-cells. So in theory, what we wanted to see was: Could our NK cells not only help to reduce the proteins, but also cool off the brain by identifying these autoreactive T-cells and eliminating them from circulation and reducing the inflammation? Again, in our AD studies, where we did CSF sampling, we were able to show the reduction of all those proteins, but also were able to show reduction in neuroinflammation measured by specific biomarkers. Glial fibrillary acidic protein was markedly reduced; neurofilament light, which is also a measure of neuronal damage and inflammation, was also reduced; and then YKL-40, which is often elevated in many neuroinflammatory and neurodegenerative diseases—we showed that our NK cells were able to reduce all of those. As such, we believe it's a much more holistic approach—that you're not only removing the proteins, but you're also removing the neuroinflammation. We believe this will lead to a much more potentially comprehensive improvement in patients’ symptoms and condition versus just targeting the proteins or a symptom.

Transcript edited for clarity.