Podcast Transcript

David Brühlmann [00:00:59]:
Parkinson’s has outlasted decades of promising therapies. So what makes a cell therapy approach meaningfully different? And could it do more than simply replace lost neurons?

In this episode, I’m joined by Bilal Fares, a neuroscience entrepreneur and co-founder of AzureCell, a venture turning a single biological insight from the University of Geneva into a translational platform. We explore the science, the ambition, and what it actually takes to build it.

Let’s dive in. Welcome, Bilal, to the Smart Biotech Scientist Podcast. It’s good to have you on today.

Bilal Fares [00:02:51]:
Same here. Thank you very much, David, for the opportunity. It’s a pleasure to talk to you today and to tell you more about our exciting mission at AzureCell.

David Brühlmann [00:03:00]:
Share something that you believe about cell therapy development that most people disagree with.

Bilal Fares [00:03:06]:
Well, it’s actually a firm conviction of mine: that cell therapy is the future of medicine—and specifically the future of medicine when it comes to the brain.

I think brain diseases are caused by the loss of cells, so they are fundamentally cellular diseases. And the only way to truly have an impact against these diseases is to replace those cells through cell therapy. That’s pretty much the basis for this conviction.

For other diseases, there may eventually be possibilities to cure them through small molecules, so the use case for cell therapy may diminish over time. But for the brain, I believe it is the future of medicine.

David Brühlmann [00:03:43]:
I’m very excited about our conversation and to explore what’s coming in cell therapy. To start us out, Bilal, draw us into your story. What first sparked your interest in biotech and neuroscience, and what have been some interesting pit stops along the way to becoming an entrepreneur?

Bilal Fares [00:04:03]:
Sure. So I actually have an interesting story, which has somehow been consistent. It hasn’t been by design—it has really been, to some extent, by chance, that destiny took me down this path.

It actually started when I was doing my master’s degree. It was focused on oncology and developing organoid models, way, way, way back. Around that time, my grandfather actually developed Parkinson’s disease. It was a really devastating moment for the family and for us because he was a very accomplished man and a role model for me and for many others. It was just devastating to see him deteriorate over time.

He personally came to me and we were talking, and he said, “You’re studying biology. I have Parkinson’s. I’m not happy with it. What is out there? Why is this happening?” I was devastated to realize that there was nothing, and that we understood so little about this disease.

That was, in a way, what drove me into neuroscience and Parkinson’s disease research. Then, somewhat by chance, I met an amazing professor who was visiting my university at the time. He was offering positions in bioengineering, focused on Parkinson’s disease. So I said, “Yes, please.”

Soon enough, I found myself at EPFL in Switzerland, doing my PhD focused on developing new models of Parkinson’s disease for drug discovery. Then another incident happened as I was finishing my PhD. The long-term business partner of my dad also had Parkinson’s disease. I remember meeting him and his son. His disease was progressing very rapidly, and it was also very heartbreaking.

I remember his son asking me, “Okay, you’re studying Parkinson’s. What have you been doing?”

And I said, “Well, we’re now able to reproduce certain features of Parkinson’s in a mouse and in mouse neurons.” He looked at me and said, “In a mouse? Okay… how does this help me? And how does this help my dad?”

For me, it became clear that we needed to move toward more human-relevant models.

That was actually the spark for my postdoc, where I stepped into stem cell biology because it made the most sense. We could now generate human neurons from stem cells in the lab for drug discovery purposes. That became the focus of my postdoctoral research.

As I was wrapping that up, my PhD advisor told me that he was starting a biotech company focused on Parkinson’s disease, translating some of the models developed in the lab, including the one I had worked on. He invited me to join as part of the early team to help build the platform.

I said, “Okay, yes.” It seemed like a good opportunity to learn. I didn’t really know what I was getting into as a co-founder at that stage.

Soon enough, I found myself going beyond R&D and beyond managing the team and the science, moving more and more toward business development. I completed my MBA along the way, which really helped me understand how to build biotech businesses.

Then Parkinson’s knocked on the door for the third time. This time, it was my father-in-law.

For him, it was difficult because, on the physical level, he complained that he woke up every morning feeling as if he had been riding a bike all night. He was so exhausted because his foot was shaking all night long.

Then there was the psychological aspect, which neither he nor his family fully understood, but I recognized. He was changing completely over time, and they didn’t realize this was part of the disease.

At one point, he said to me, “Bilal, you’ve been studying Parkinson’s for more than 10 years now, and you’re part of a company. What are you doing? Where is this therapy? When is it going to come? Are there any clinical trials that can actually change my life?“

That was when I started to rethink everything and look carefully at the current therapeutic landscape. It hit me that cell therapy is the future. It was the only thing I could honestly recommend to him as something that had the potential to change his life.

Of course, there’s deep brain stimulation, which is almost like magic. Once it’s turned on, patients can respond dramatically well. But it comes with risks because it’s a permanent implant in the brain, and over time it may stop working. Cell therapy, on the other hand, is the logical way to restore what has been lost in the brain.

I realized that this field is still so early and has so much potential. It has already benefited enormously from the work of pioneers in the field, but there is still tremendous opportunity to improve it by enhancing the durability of transplanted cells, improving their initial survival, optimizing production processes, and increasing safety.

I wanted to be part of that. That was the point when I decided to start working on AzureCell.

David Brühlmann [00:08:27]:
Wow, what a story. Very powerful. Given what you’ve experienced with people living with this devastating disease, Parkinson’s, your company’s slogan becomes even more powerful: “Restoring neural function is just the beginning.” What does that mean for you?

Bilal Fares [00:08:46]:
Maybe starting from the end, Parkinson’s and other neurodegenerative diseases are caused by the loss of cells. This loss is massive. In advanced stages, you can have a 95% loss of dopaminergic neurons. Cell therapy is the only therapeutic modality that allows us to restore what has been lost—to replace those lost cells.

But now, through the power of genetic engineering, we can think about possibilities where we don’t just restore what has been lost—not only replacing those 95%—but also use these transplanted cells to produce therapeutics within the brain that protect the remaining neurons.

This is becoming increasingly feasible with advances in genetic engineering and therapeutic development. Beyond that, you can also think of cell therapy as a modality where you don’t necessarily need to restore function. Instead, you simply need sufficient bioavailability of therapeutics within the brain.

Right now, one of the major limitations in developing therapies for the brain—especially large molecules—is the blood-brain barrier.

As cell therapies become more established, one can envision using them as a way to deliver therapeutics directly into the brain.

In that scenario, you’re not necessarily restoring neural function for certain diseases, but instead ensuring continuous modulation of the pathogenic mechanisms occurring within the brain.

If we think even further into the future—and perhaps move a little into science fiction—we can imagine cell therapy not only restoring function or modulating disease processes after they begin, but even serving as a preventative treatment.

As cell therapies become safer, more mature, more cost-effective, and easier to manufacture, you could imagine that, at a certain age, people receive transplanted cells that help prevent these diseases from developing in the first place.

David Brühlmann [00:10:35]:
Wow, that’s very powerful. Tell us about the platform you’re using. You’re combining stem cell technology with genetic and cell engineering. How does that actually work?

Bilal Fares [00:10:48]:
The key innovation we have right now focuses on the neuroprotection of engrafted cells in the brain. Right now, once cells are transplanted into the brain, only 3% of what you transplant survives the process.

David Brühlmann [00:11:03]:
Oh wow. That’s significant.

Bilal Fares [00:11:05]:
And then, from those surviving cells, only 10% become terminally differentiated neurons that are actually functional and capable of restoring neural function.

Then, even among those remaining 10% of the 3%, the cells remain susceptible to the same disease mechanisms that killed the original neurons in the first place. It’s as if there’s a fire in the brain that destroyed 95% of the cells. You’re replacing those cells, but you’re placing the new cells back into the same fire.

Our lead innovation at the moment is a novel neuroprotective protein that we’ve identified. When we overexpress this protein in the transplanted cells, it enhances their survival at multiple levels.

More importantly, it specifically protects against four different mechanisms that drive Parkinson’s disease. In effect, we’re giving the transplanted cells a shield against the fire, helping ensure that they survive over the long term.

In addition, we have several technologies in development to improve the safety of transplanted cells, ensuring that any unwanted proliferating cells do not remain in the brain. If such cells do appear, we have a mechanism to selectively eliminate them.

We also have an exciting manufacturing platform developed by a very talented postdoctoral researcher in the lab. It enables the production of neurons directly from stem cells in a single step. She is now spinning this technology out into her own company, and we’re exploring a partnership with her to use this platform for cell therapy manufacturing and production.

David Brühlmann [00:12:29]:
How do you produce these cells, and then how do you administer them to a patient once they’re ready?

Bilal Fares [00:12:38]:
We believe that the future of cell therapy is allogeneic—that you need to have off-the-shelf cell banks that different patients can benefit from.

There’s an advantage in the brain because it’s immune-privileged to some extent. With immunosuppression for a 6- to 12-month period, transplanted cells can survive over the long term.

So that’s one aspect.

Our approach is to use iPSC-derived, genetically modified cells, differentiate and specify them into neuronal precursors, cryopreserve them, and then administer them through stereotactic transplantation into the brain, targeting specific regions. It would essentially be a one-shot treatment.

David Brühlmann [00:13:17]:
But you would need to perform surgery in order to implant them into the brain, right?

Bilal Fares [00:13:22]:
Yes, that’s the only way.

David Brühlmann [00:13:23]:
That’s the only way because of the blood-brain barrier, right?

Bilal Fares [00:13:26]:
Yes, and because you also need the cells to be in a very specific location within the brain, where they can integrate into the neural circuitry, release dopamine at the required levels, and begin restoring function.

David Brühlmann [00:13:35]:
How would that work for patients whose disease has already progressed significantly? You mentioned that 90% or even more of the cells are gone. Could that still be done as a one-shot treatment, or would it be much more complicated?

Bilal Fares [00:13:47]:
It could still be a one-shot treatment, provided you’re able to ensure that the transplanted cells survive over the long term. That’s precisely what we’re trying to achieve right now.

The patient population that everyone is targeting with cell therapy for Parkinson’s consists of patients with moderate to advanced Parkinson’s disease, where there has already been substantial neuronal loss.

The reason is that you have a much better chance of observing a clinical effect because dopamine levels have been significantly depleted. If you transplant cells that restore dopamine production to a meaningful level, you’re much more likely to see beneficial clinical outcomes.

That’s why this patient population is currently the most suitable for these therapies.

David Brühlmann [00:14:22]:
Where are you currently in terms of clinical development, and also with respect to manufacturing—the CMC side of things?

Bilal Fares [00:14:31]:
Right now, we’re at the preclinical stage. We have very strong proof-of-concept data for each of the enabling technologies that I mentioned. We’ve also just completed the engineering of an R&D-grade cell line that has a corresponding GMP iPSC sister line. We’re currently validating the proof of concept for efficacy, potency, and safety in this line before translating everything into GMP manufacturing and moving toward IND-enabling studies.

From the CMC perspective, we’ve engaged leading experts in cell therapy development, specifically for the brain and Parkinson’s disease, but also beyond Parkinson’s, to leverage existing know-how from other indications.

Our goal is to establish the most cost-effective and time-efficient path to an Investigational New Drug (IND) application. Our strategy is to focus internally on what we do best—early preclinical development—and partner with the best organizations for process translation and GMP manufacturing. We’re currently in discussions with several potential partners who could support us throughout that process and help accelerate our path to an IND.

David Brühlmann [00:15:36]:
As you said before, there are not many treatment options available for Parkinson’s disease. Parkinson’s has defeated many therapeutic approaches over the decades. You’ve made a strong case for cell therapy. Why are you so confident that your approach to cell therapy will work, considering that so many previous therapeutic developments have failed?

Bilal Fares [00:15:57]:
Again, just to briefly recap: Parkinson’s is fundamentally a cellular disease. You have a significant loss of neurons.

The current standard of care is largely symptomatic. These therapies boost the activity of the remaining neurons—essentially enhancing the function of the final 5% that remain.

Up to a certain point, this works. But because these treatments don’t interfere with the disease mechanisms that are killing those neurons, patients continue to lose even that remaining 5% over time. Eventually, these therapies either stop working or become very difficult to dose appropriately. That’s the current state of the art: symptomatic treatments that temporarily enhance the activity of the remaining neurons.

Over the past 20 to 30 years, another class of therapies has emerged with the goal of protecting those remaining 5% of neurons. The idea has been to preserve them while continuing symptomatic treatment. Unfortunately, that strategy hasn’t been successful. There have been many failures in this area.

I think one reason is that many of these therapies have treated Parkinson’s disease as though it were driven by a single pathological mechanism. We’re increasingly understanding that Parkinson’s is a highly complex disease involving multiple interconnected pathogenic mechanisms.

Because of that complexity, developing therapeutics that target only a single pathway has become increasingly challenging, and those approaches haven’t been able to protect the remaining neurons.

The second major limitation is drug delivery. Even if you have a very effective therapeutic—especially a complex biologic—it’s extremely difficult to deliver it to the brain because of the blood-brain barrier. For example, antibody-based therapeutics perform exceptionally well in in vitro and in vivo models when sufficient concentrations reach the brain.

However, recent clinical trials have faced major challenges because of the blood-brain barrier. When antibodies are administered systemically into the bloodstream, less than 0.1% of the administered dose reaches the brain. And from that tiny fraction, it’s difficult to know how much actually reaches and engages the intended target.

So it’s perhaps not surprising that many of these therapies haven’t produced the desired clinical benefit. Cell therapy is fundamentally different. Initially, we don’t focus primarily on preserving the remaining 5% of neurons. Instead, we aim to replace the 95% that have already been lost. But what makes cell therapy particularly exciting is that, through genetic engineering, those transplanted cells can also be designed to protect the remaining neurons.

That makes cell therapy a much more comprehensive therapeutic modality—one that has the potential not only to restore function through cell replacement but also to modify the course of the disease in future generations of these therapies.

David Brühlmann [00:18:18]:
So cell therapy could also be the solution for other diseases like Alzheimer’s disease or other neurological disorders, right?

Bilal Fares [00:18:26]:
I would say yes. The concept is that for any disease involving the loss of cells, if you’re able to regenerate and replace those cells, you should have a therapeutic impact.

I would say that Parkinson’s disease is where cell therapy programs are currently the most advanced because, to some extent, it’s the simpler indication to address with cell therapy.

That’s because you lose a specific population of cells in a very specific location, and those cells have a very specific function: releasing dopamine. They don’t require an especially complex anatomical architecture or circuitry to restore that function.

For Alzheimer’s disease, on the other hand, you’re dealing with much more widespread neuronal loss throughout the brain. You’re also dealing with memory, which remains, to some extent, a black box. We still don’t fully understand how memories are formed, stored, retrieved, and maintained.

In addition, there are highly complex neural architectures involved—for example, within the hippocampus, the different cortical layers, and other interconnected brain regions. I believe cell therapy for Alzheimer’s will come, but it will simply require more time.

There are already investigational cell therapy programs for Alzheimer’s disease, but they are not as advanced as those for Parkinson’s disease or for other neurological disorders that are somewhat simpler to address.

David Brühlmann [00:19:31]:
Moving beyond cell replacement isn’t just a slogan—it’s a different way of thinking about how we restore neural function. Bilal Fares showed us why the science and the platform have to evolve together. There’s more ahead, in Part Two, where we dive deeper into the manufacturing challenges and the entrepreneurial realities of building a cell therapy company.

If this conversation gave you something valuable, please take a moment to leave a review on Apple Podcasts or your favorite podcast platform. Thank you for tuning in, and we’ll see you next time.