Prescriptions for accelerating neuroscience translation: Q&A with Mustafa Sahin, MD, PhD

Mustafa Sahin Translational Neuroscience CenterMustafa Sahin, MD, PhD, a neurologist at Boston Children’s Hospital, directs the Translational Neuroscience Center, which he founded several years ago to accelerate neuroscience research to the clinic. He also directs the hospital’s Translational Research Program. In this interview with Boston Children’s Technology and Innovation Development Office (TIDO), Sahin talks about his motivations as a clinician-scientist and how he works with industry partners to move discoveries forward.

What drives you as a scientist? 

What drives me as a scientist has changed over the course of my career. It was my fascination with experimentation that first got me interested in biology. In high school, I took vials of fruit flies to a radiation oncology department and tested the effects of radiation on the mutation rate. When I came to the U.S. to study biochemistry in college, I was drawn to the mysteries of the brain. While my PhD and postdoctoral work continued on very fundamental questions about how neurons connect to each other, advances in genetics and neuroscience allowed me to bring rigorous basic science approaches to clinical questions. So more and more, my science is driven by a need to bring treatments to the patients I see in the clinic. Fortunately, this is no longer a long-term, aspirational goal, but something within reach in my career.

What is unique about your research? 

While not unique to me at Boston Children’s, an important aspect of my research program is designing experiments with the goal of accelerating our ability to treat patients.

What unmet needs does your research aim to solve? 

The need for better treatments for neurodevelopmental disorders. Through the Human Neuron Core, we test FDA-approved compounds through a screening library on induced pluripotent stem cells (iPSCs) that have been differentiated into neurons. We also conduct phase II/III clinical trials of novel compounds for multiple neurogenetic disorders. We hope through these multiple initiatives to repurpose existing drugs and identify novel treatments.

A Purkinje cell made from a patient with tuberous sclerosis (Maria Sundberg)

What tools are you developing to better study neurological diseases?

About five years ago, when the first clinical trials in neurodevelopmental disorders were starting to come online, we realized that we did not have a well-organized infrastructure in neurosciences for bringing therapies from the lab to the clinic in an efficient manner. Every investigator had to develop their own team to overcome commonly faced obstacles. So, we developed the Translational Neuroscience Center (TNC) from the bottom up to facilitate translational studies in neurodevelopmental and neuropsychiatric disorders, neuromuscular diseases and pain.

cortical neurons SPG47
Cortical neurons with the SPG47 mutation (Robin Kleiman)

Through the TNC, we now have platforms to help investigators all the way from target discovery to Phase II clinical trials. For example, our Human Neuron Core can facilitate target identification, validation and drug screens. Our Electrophysiology Core can perform parallel EEG-based studies in animal models and patients. Our Regulatory Core can help investigators with IRB and FDA submissions and project management. Our Human Neurobehavioral Core Services can provide expert, detailed phenotyping for cognitive/behavioral outcome measures.

With these enhancements, we are now in a position to take the lead on performing clinical trials in children with nervous systems disorders.

What’s your favorite tool or model?

I am not a scientist who has a favorite model or tool. We have let the disease, in my case tuberous sclerosis, guide us from model to model, tool to tool as necessary. Animal models, in particular genetically engineered mice, have been the mainstay of our research. However, they have some significant drawbacks, so we have increasingly turned to human neurons in a dish as an additional model. Last year, we published two papers where we used a combination of mouse experiments and human neurons. I think this combinatorial approach will be even more powerful than either one alone.

How can studying pediatric neurological diseases inform the study of adult diseases?

In several ways. First, many of the cell biological processes we study in pediatric neurological diseases such as tuberous sclerosis have important roles in adult neurodegenerative diseases as well. These include autophagy, mitochondrial dynamics, endoplasmic reticulum stress, oxidative stress, synapse pruning, etc.

Second, given the early plasticity of the brain, the therapeutic window for treatments is likely to be in infancy and childhood, allowing us to alter disease progression. The same concept is likely to apply to at least some adult neurological diseases, too.

Finally, because pediatric diseases affect developing brain/neurons, they may be easier to model in animal models (that do not live for decades) or in cell culture. So, investigating and screening for compounds in pediatric neurological disease models may give us insights and therapies for some of the adult disorders as well.

How can academia better de-risk technologies for industry development?

Industry is in search of drugs with reasonably large effect sizes that are reproducible in one or more models. The incentives in academia (rapidly publishing high profile manuscripts) often do not align with industry’s ultimate goals. Many academic publications use a drug only in one concentration, do not demonstrate target engagement in the target organ and do not provide pharmacokinetic (PK) information. Through both our Translational Research Program grants and the activities of the TNC, we have been working towards addressing this gap.

Mustafa Sahin Jonathan Lipton Translational Neuroscience Center
Sahin in the lab with Jonathan Lipton, MD, PhD

The TNC offers a drug-discovery mini-course that focuses on neuroPK for academic investigators. In every experiment in the TNC Neurophysiology Core, we urge the investigators to measure brain PK and target engagement as much as is feasible. We hope these efforts will not only de-risk targets and drugs for industry, but also make our studies more reproducible, with higher translational impact.

You’ve collaborated with biotechs large and small. What is most important for a successful collaboration? What has each side brought to the table, and how has each benefited?

Academic-industry partnerships are key in rare disorder research. We do much of the early preclinical work at Boston Children’s, and are also fortunate to care for patients with rare diseases from across the world who can be enrolled in research. Industry has been helpful in coordinating the large Phase III clinical trials amongst multiple hospitals nationally and internationally. We have also done a number of projects with companies in our Human Neuron Core.

In all of these cases, involving the Technology & Innovation Development Office and the Clinical Trials Business Office has been essential for success, allowing for clear deliverables and streamlining communication with sponsors. The most successful collaborations have been those championed by scientists on both sides. Often, we bring models (animal or cell models developed at Boston Children’s) and the company brings novel compounds that we could not access otherwise. Together, we are able to probe biological problems in a way we cannot in either setting alone.