In January, we announced our 2020 Innovator Award grantees. The Innovator Award is designed to provide seed funding for bold and innovative work with the potential to transform hydrocephalus research. In this installment of our Meet the Innovator Award Grantees Blog Series, we interviewed Dr. Aditya S. Pandey, one of four scientists who received a 2020 Innovator Award. Dr. Pandey is a Professor of Neurological Surgery at the University of Michigan. Dr. Sravanthi Koduri, a resident and fellow who is actively involved in this research project, also participated in the interview. Their research aims to test if acetazolamide (Diamox), when put directly into the ventricles, can block the activity of the carbonic anhydrase and thus prevent hydrocephalus.
What sparked your interest in hydrocephalus research?
I specialize in cerebral vascular neurosurgery and use open surgical as well as endovascular techniques in treating vascular diseases of the brain and spinal cord. One of our main patient populations are those who suffer from bleeding within the brain. These bleeding episodes can occur secondary to multitude of reasons but most commonly are related to fragile blood vessels or trauma. One of the common side effects of brain bleeding is the development of fluid build-up within the ventricles thus leading to hydrocephalus. Since a great proportion of our bleeding stroke patients suffer from hydrocephalus and there is no cure or preventive strategy, we aim to determine the role of key blood products in the development of hydrocephalus. If we could only understand how hydrocephalus takes place after someone has a bleed in the brain, you could devise medications to prevent it or even medically treat it. The current project represents a great opportunity for us to be able to help the bleeding stroke patient population.
How long have you been researching hydrocephalus?
Over the last 15 years, I have been focused on the treatment of those with bleeding strokes including studying factors that lead to better surgical outcomes as well as developing minimally invasive ultrasound based technologies and medical therapies for treating those with bleeding strokes. We have evaluated our own series of bleeding stroke patients which showed that the presence of blood within the brain ventricles is a strong predictor of hydrocephalus formation. Over the last seven years, Sravanthi and I have been collaborating with a tremendous group of colleagues, Drs. Xi and Keep, in developing an animal model that allows us to take fluid samples from bleeding stroke patients and inject it into murine ventricles to identify which toxins in the human cerebrospinal fluid leads to hydrocephalus formation. By identifying the particular hydrocephalus causing factors, we will aim to develop medical therapies to counteract such toxins and thus to prevent and treat hydrocephalus.
What is the goal of your research funded by the Innovator Award Grant? What questions do you hope your research will answer?
When bleeding takes place in the brain, the red blood cell leaks out within the brain and within the fluid spaces of the brain. Over time as that red blood cell dies, the contents inside the red blood cell spills out into the brain causing brain injury including the development of hydrocephalus. One of those toxins is carbonic anhydrase. When the carbonic anhydrase is inside the cell it maintains the livelihood of that cell. When it leaks out, carbonic anhydrase can potentially initiate toxicity and injury to the brain, which causes fluid to build up. Our hypothesis is that carbonic anhydrase, independently of everything else, can cause hydrocephalus, and that negating its effects with a medication is going to reduce the effects if not hopefully get rid of hydrocephalus in its entirely. With the Innovator Award grant, our goal is to understand what degree of hydrocephalus is caused in animals post injection with carbonic anhydrase.
One of the great things about carbonic anhydrase is that there is already a medication, Diamox, that can neutralize its effects. So if we inject this toxin, carbonic anhydrase, and it leads to hydrocephalus in animals, can we prevent hydrocephalus by injecting the antidote, Diamox? If we can show that, this will form the preliminary work to then ask the question: is it feasible to inject Diamox into the ventricle of bleeding stroke patients and prevent hydrocephalus? The eventual goal is to validate the injection of Diamox into the fluid spaces of the brain as a treatment method for hydrocephalus, and hopefully provide a therapeutic measure for patients in the future.
If our animal studies show promising results, we will be able to use the preliminary data to conduct clinical trials to really see if Diamox injection into the ventricles can prevent or treat hydrocephalus. Such a development could serve as a major step towards medical therapy for hydrocephalus as currently the only treatment involves surgical placement of shunts or creation of communicating paths between the fluid spaces. There are many parts of the world where patients suffer a hemorrhagic stroke and develop hydrocephalus but neurosurgeons aren’t necessarily available or the equipment isn’t there, or surgery is performed and works for a period of time but eventually the shunt system clogs up and the patient is unable to have repeat surgeries. Thus developing a medical therapy like Diamox has the potential to reach millions of patients and prevent the need of surgery in many.
What makes your project unique?
The most unique aspect of our project is the method of delivery. There have been many studies evaluating IV and oral use of Diamox with equivocal results; however, we aim to place Diamox into the ventricular space where the presence of blood is linked to the formation of hydrocephalus. The more direct application of the potential antidote within the region of interest could lead to prevention of hydrocephalus.
Intravenous and oral administration of medications are prevented from entering into the fluid spaces of the brain given the blood brain barrier prevents large molecules from entering into the spaces of the brain. Thus Diamox is not able to cross into the brain and so by delivering the medication directly into the fluid space of the brain we hope to achieve higher concentrations at the site of injury.
The first aim of our study is to understand what toxicity is caused by the carbonic anhydrase within the brain fluid spaces. If we find that there is significant injury including hydrocephalus formation in our animal models, we will have the opportunity to be able to block with Diamox to see if hydrocephalus is prevented.
How important is HA’s Innovator Award grant for your project?
Projects like this are expensive requiring significant effort and time. It’s a tribute to Sravanthi, her interest and hard work, as well as us having the resources from the Hydrocephalus Association to complete this innovative project. The Hydrocephalus Association, through the Innovator Award, has allowed us to take on a high-risk, high-reward project with the goal of developing a medical therapy for hydrocephalus treatment and prevention.
What are the next steps?
We are currently determining the optimal dose of carbonic anhydrase which leads to the greatest hydrocephalus formation. Once this is achieved, we will inject the carbonic anhydrase mixed with the antidote, Diamox, to see if the hydrocephalus formation is prevented or diminished.
If we have a positive finding – that injecting the carbonic anhydrase leads to hydrocephalus, and if we mix with Diamox then it prevents hydrocephalus – then we will utilize the findings toward a clinical trial. The goal would be to design a clinical trial evaluating the safety of injecting Diamox into the fluid spaces of patients with bleeding strokes. We hope that our project, made possible through the Innovator Award from the Hydrocephalus Association, represents a first step towards developing medical therapies for preventing and treating hydrocephalus.