I have a PhD in mechanical engineering with specialization in biofluid mechanics, and I conducted postdoctoral work in CSF mechanics and physiology at the Swiss Federal Institute of Technology. My interest in the field was originally sparked by a brain disorder called Chiari malformation, a condition in which brain tissue extends into the spinal canal.
I decided to join Alcyone two years ago and focus on the company’s FalconTM precision central nervous system (CNS) delivery platform technology because I wanted to have a direct impact on the lives of patients and their families. The ability to deliver a therapeutic to the brain with efficiency and precision is a Holy Grail for successful treatment of complex neurological conditions like Rett syndrome.
Why is understanding cerebrospinal fluid important for the development of genetic-based treatment for Rett?
At Alcyone and across the biopharmaceutical industry there is consensus that the key to successful gene therapy lies within delivery. In other words, we have therapies out there that have shown tremendous promise in the lab, including X reactivation, the approach that Alcyone is working on for people with Rett. But to see real benefits from any genetic-based therapy, we need it to reach the right targets in the brain, while also avoiding regions we don’t want to hit. To make things more complex, our bodies are designed to protect the brain with the blood-brain barrier, which tightly regulates what enters the brain from the blood stream.
For this reason, Alcyone has focused on delivering ACTX-101, its Rett treatment, into the cerebrospinal fluid, a region that essentially bypasses the blood brain barrier. ACTX-101 is a gene regulation therapy that reactivates the silenced X chromosome, where the functional MECP2 gene resides, in girls with Rett.
Our research in CSF dynamics is applied to the company’s precision delivery platform, a proprietary technology that we call Falcon™, which we believe can optimize delivery for a specific disease. For Rett, we will examine the ways in which the bodies of Rett patients are different, leading to different patterns of CSF movement, using computer models. We then optimize our delivery system and drug infusion algorithm to work within the unique anatomy and CSF dynamics of Rett patients to target the drug to regions we want to reach, and away from regions we want to avoid.
We believe this approach toward delivery is the evolution needed to address some of the industry’s current delivery challenges.
What exactly is different about delivering treatments to the brain in people with Rett syndrome?
People with Rett have unique anatomical conditions, especially in the spine. These conditions include reduced cerebral volume and increased CSF volume around the intracranial space. In addition, people with Rett also have respiratory abnormalities. Therefore, it is expected that delivery of a medication in the CSF for a Rett patient could be different than for a typical person, presenting unique challenges. We know we must ensure our therapeutic reaches particular regions within the brain to be most effective, so we consider the unique anatomical and physiological conditions of Rett as an important component of treatment with ACTX-101.
At Alcyone we believe optimizing delivery is equally important as the therapy. Our work is focused on getting that delivery just right, and this is what excites me about the work we do.
What else should Rett parents and the Rett community know about cerebrospinal fluid? What do you find fascinating about it?
The CSF is really an amazing part of human anatomy and thoroughly caught my attention when I first started researching it more than 20 years ago.
Many people know that the CSF acts as a shock absorber, cushioning the brain within the skull and the spinal cord from trauma. What people may not know is that the CSF supplies nutrients to nervous system tissue and removes the waste products that result from cerebral metabolism. The CSF undergoes a complete renewal at least four to five times each day in the average young adult, and some studies are showing that continuous fluid exchange with the brain tissue could be much higher. It might even change depending on whether a person is awake or asleep.
People probably don’t know that the CSF has its own rhythm, like the heartbeat. It is even thought that a reduction in CSF turnover may contribute to the accumulation of metabolites that is seen in aging and neurodegenerative diseases. The composition of CSF is strictly regulated, and any variation can be useful for diagnostic purposes.
I think that as scientific understanding about the CSF system progresses, we are going to find it is just as important as blood circulation or the lymphatic system. By understanding it deeply we will unlock better understanding of many CNS diseases, which will lead to new therapeutic options and interventions, just like we have seen over the years with insights into blood circulation.
What other industries or activities need to understand CSF, and what other projects are you working on?
There are many conditions for which understanding of CSF is desperately needed, such as spina bifida, meningitis, multiple sclerosis, Alzheimer’s, ALS, and many other CNS diseases, but one of the most unexpected groups that will benefit from CSF study is astronauts!
It appears that living in environments with very little gravity for prolonged periods somehow disrupts the normal flow of body fluids and intracranial dynamics; we’ve observed this in a majority of long-duration spaceflight astronauts. We do not know yet exactly why, but we believe that the disruption to the flow of CSF results in permanent damage to the eye, a disorder termed “spaceflight-associated neuro ocular syndrome.” One day NASA plans to send humans to Mars, but if by the time the astronauts arrive they have permanent eye damage, to the point of partial or even complete blindness, that would be a big problem.
Our team is working with NASA in collaboration with researchers from around the world to understand how the eye is being damaged and what role CSF dynamics play in the process.
What can you share about Alcyone’s Falcon precision delivery technology and how it solves the delivery challenges?
Falcon™is our proprietary technology-enabled modular platform that allows for safe, scalable, and targeted delivery to CNS regions. The therapeutic is administered through a bedside syringe pump that is programmed with the infusion algorithm developed specifically to target the regions of interest in the brain. Falcon integrates knowledge from our study of CSF fluid dynamics, our unique capabilities in CSF computational modeling, and bioengineering. This approach helps us to understand how a drug moves through the CSF, especially within complex CSF physiology like Rett. We then take that information to determine the infusion algorithms needed to preferentially target the drug towards the regions of interest in the CNS (into the brain) via safe lumbar intrathecal access.
We envision our Falcon precision delivery platform transforming the possibilities for CNS drug delivery. It’s exciting work and it will be rewarding to see it make a difference for people living with complex neurological conditions like Rett.
What research milestones should the Rett community be looking out for when it comes to Alcyone’s work on ACTX-101 and treatment delivery?
In general, any new discoveries being made in CSF dynamics will help us optimize the delivery of treatment. Right now, we are studying ACTX-101 in animals. Currently, we are working through pinpointing the appropriate drug volume and optimal dosing conditions that consider the anatomical complexities of the condition. We work closely with the Rett community through RSRT and other organizations to incorporate the voice and experience of people living with Rett. These experiences will guide our clinical trial design and development plan as we move forward.
To learn more about ACTX-101 and Alcyone's work, watch our webinar, "Introducing ACTX 101, a Gene Therapy for Rett Using X Reactivation Technology."