Dr. Hassan Al Ali’s Contribution to the Evolving Landscape of Drug Discovery
Summary
- The University of Miami Miller School of Medicine’s Dr. Hassan Al Ali is using advanced mathematics and algorithms to refine drug discovery work.
- Dr. Ali’s career in Miami began at The Miami Project to Cure Paralysis, where he worked with Dr. Vance Lemmon and Dr. John Bixby on investigating ways to promote axonal growth in spinal cord injuries.
- Dr. Ali’s success and approach led to collaborations with researchers studying lymphoma, kidney disease, ALS and more.
When Hassan Al Ali, Ph.D., associate professor of neurological surgery at the University of Miami Miller School of Medicine, first came to Miami, he was searching for more than just a new research home. He was looking for a place where bold ideas could reshape the future of medicine.
Today, as director of the Drug Discovery Core at The Miami Project to Cure Paralysis, Dr. Ali is recognized for influencing how scientists discover new therapies for spinal cord injuries, cancer and beyond. His work has been supported by grants well in excess of $10 million, from the National Institutes of Health and the U.S. Department of Defense, as well as industry, institutional and private sources.
Drawn to Miami: A Meeting of Minds
After completing his Ph.D. in biochemistry, Dr. Ali wasn’t sure whether his career in drug discovery would be in academia or industry. That changed when he met neuroscientists Vance Lemmon, Ph.D., and John Bixby, Ph.D., at The Miami Project. They were investigating kinases, which were predominantly pursued in cancer research, to promote axonal growth in patients with spinal cord injuries.
“People were under the impression that kinase inhibitors were strictly cancer drugs,” Dr. Ali said, but The Miami Project had a different question in mind. “How do you come up with a drug that can modulate kinases in a way that is not toxic and can reprogram the central nervous system to heal itself? Vance Lemmon and John Bixby were pioneering a new area in neuroscience.”
This meshed well with Dr. Ali’s background in kinase biochemistry and his desire to wield this privileged family of genes for drug discovery and development.
The Miami Project’s openness to innovative ideas and advanced technology, like automated microscopes and robotic liquid handling, was a major draw.
“At the time, these were things you’d find in biotech, but not in academia,” said Dr. Bixby. “Hassan immediately saw this as a way to discover drugs the way biotech companies do.”
Rethinking Drug Discovery: From One-to-One to Network Solutions
Traditional drug discovery often focused on a “one compound, one target” approach. Dr. Ali saw the limitations of this view.
“For a lot of diseases and disorders, it’s not sufficient to engage a single target,” he said. “The biology of the cell is very complex. It’s like the internet. If you take out one server, it’s not enough to modulate the whole system.”
The kinase inhibitor compounds Dr. Ali was studying might deter any combination of the 500-plus kinases in the human kinome. Dr. Ali needed a strategy for large-scale differentiation. He turned to Houssam Nassif, a college friend who was developing algorithms for music video recommendations at Amazon.
“It was a similar problem to what he was working on at Amazon, which was, ‘If you like this, you’re likely to like that,” Dr. Ali said. “We put our heads together to figure out how to use the data from phenotypic screens to identify the targets.”
Dr. Ali wrote the first version of a custom, machine-learning algorithm, which Nassif then vetted and refined. Their approach mathematically deconvoluted the effects of each inhibitor, cross-referencing the kinases each compound hit with the observed biological outcomes, such as axonal growth. The integrative platform of phenotypic screening, biochemical profiling and advanced machine learning (called idTRAX) enabled Dr. Ali’s team to identify not just single drug targets but networks of targets and their interactions.
“We started finding combinations of kinases that, if you co-inhibit, you make the axons grow substantially longer,” Dr. Ali said. “Inhibiting or targeting one gene wasn’t enough. We found genes that were synergistic. If you inhibited them at the same time, you got effects—more axon growth than anything we’d seen up to that point. We were able to accomplish something that none of those technologies, used separately, could do.”
“The major insight was the combination of using reagents that are multi-specific and computationally combining all that information to identify the kinases that are important,” said Dr. Bixby.
And not just important to spinal cord axon regeneration. Dr. Ali and team had created a system that was as versatile as it was new.
“I want to emphasize how powerful it is, as an approach,” Dr. Lemmon added. “Their mathematical insight combines information about a whole bunch of kinase inhibitors and all the kinases they inhibit. That’s a completely different approach than trying to find a dozen inhibitors of kinase A and a dozen inhibitors of B, which wouldn’t work because you’d only be inhibiting one kinase at a time. Hassan’s solution can be applied to really complicated problems.”
Dr. Ali is developing a therapeutic candidate for spinal cord injury based on this work. Funded by a cooperative UG3/UH3 grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the project will reach Phase 1a clinical testing in 2026 or 2027. If all milestones are crossed, this program will provide as much as $10 million of funding support to translate the discovery into a clinical drug.
A Return to Cancer
Dr. Ali has maintained a keen interest in oncology research, where his platform proved beneficial, as well. He reached out to Jonathan Schatz, M.D., a researcher at Sylvester Comprehensive Cancer Center, part of the Miller School, and professor in the Division of Hematology at the Miller School, to gauge the applicability of idTRAX to diffuse large B-cell lymphoma, the most common lymphoma type.
“Hassan’s angle on it was different,” Dr. Schatz said. “He was coming at it from a target hypothesis-agnostic point of view.”
The two scientists used the platform’s computational power to quickly find both promising and problematic targets, accelerating the drug discovery process.
“The novel machine learning-enabled approach was designed not only to find the desirable targets that you want your drug to inhibit, but also the undesirable targets that you need your drug to avoid,” Dr. Schatz noted. “It allowed us to eliminate compounds that promote cancerous growth.”
The collaboration yielded the discovery of a new target for lymphoma therapy, the cyclin G-associated kinase (GAK). Dr. Ali and Dr. Schatz are co-principal investigators for a National Institutes of Health R01 grant-funded study looking more deeply into GAK. And they’ve extended their collaboration to live imaging of tumor cells that tracks cell changes over time.
“We make videos that show the way the cells are changing every 10 minutes,” Dr. Schatz said. “Hassan can then feed that data into a feature extraction algorithm that tells us what the drug is doing to the cell and apply machine learning for a detailed comprehension of what’s going on.”
Similarities Between Spinal Cord Injury and ALS
Dr. Ali’s innovative drug discovery program was the foundation of a fruitful collaboration with the Miller School’s Zane Zeier, Ph.D., a Miller School associate professor of psychiatry and behavioral sciences, as well.
The two scientists’ work shared a similar goal—proaxonal regeneration—albeit for different challenges. Dr. Ali’s success in compelling regeneration for spinal cord injuries piqued Dr. Zeier’s curiosity. He was trying to do much the same for amyotrophic lateral sclerosis (ALS) and knew that the same corticospinal axons affected in spinal cord injury also degenerate in ALS.
That made the therapy a logical candidate for repurposing in ALS research. Additional investigation revealed that the molecule developed by Dr. Ali targets both axonal degeneration and neuronal death.
“Dr. Ali’s molecules were identified for their pro-axonal growth effects, but they are also neuroprotective,” said Dr. Zeier. “That’s when I became very excited, because there is a strong rationale for these targets in the field of ALS.”
The two received early-stage drug discovery funding from the U.S. Department of Defense to find out if Dr. Ali’s molecule could address the neuropathology in ALS. Their work combines Dr. Ali’s advanced calculations with Dr. Zeier’s expertise in induced pluripotent stem cell disease modeling.
“In a complex disease like ALS, a therapy likely has to be multi-functional, to address multiple disease features,” said Dr. Zeier. “Hassan’s strategy of embracing polypharmacology allows a single molecule to inhibit multiple targets and therefore have a larger impact on disease processes.”
Halfway through the two-year project, Dr. Zeier reported promising results.
“We are confident that the molecule retains its proaxonal growth and neuroprotective effects in ALS models,” he said.
An Entrepreneurial Turn
Discoveries of compounds that deter disease are laudable achievements in and of themselves. But to truly make an impact, these breakthroughs need to find patients. They need to move from the bench to the bedside.
Dr. Ali’s collaboration with Alessia Fornoni, M.D., Ph.D., professor of medicine and assistant dean for research training and development at the Miller School, is making that move. They head up the Miller School’s drug discovery task force that investigates new therapies across the medical spectrum and pursues industry partnerships to bring discoveries to market. Dr. Fornoni, in fact, played an integral role in convincing Dr. Ali to accept a faculty position at the Miller School rather than work for the private pharmaceutical companies that were aggressively recruiting him.
Dr. Fornoni, director and chair of the Peggy and Harold Katz Family Drug Discovery Center, is an internationally acclaimed kidney researcher. Her work demonstrated the relationship between lipid droplets in cells and kidney disease. Dr. Fornoni worked with Dr. Ali to develop a phenotypic assay to screen more than 45 million unique small molecules and identify a compound series that effectively reduces lipid droplet accumulation in stressed podocytes.
She’s optimistic the discovery, catalyzed by Dr. Ali’s approach, could lead to new, personalized treatment strategies for patients with a variety of genetic kidney mutations.
“This unique platform that he developed allows investigators from fields outside of neuroscience to benefit,” Dr. Fornoni said.
Just as importantly, both researchers understand the importance of looking outside academia to position therapies to do the most good for patients. Drs. Ali and Fornoni have already secured a patent for the compounds they developed. Now they’re looking to private industry to accelerate their development.
“It’s the bread and butter of drug discovery,” Dr. Fornoni said. “There is no such thing as drug discovery using only institutional dollars. The path forward is to speak to investors.”
“The polypharmacology platform was recognized as novel and highly innovative early on, but from an industry perspective, the team was ahead of its time,” said Norma Sue Kenyon, Ph.D., professor of surgery, microbiology, immunology, biomedical engineering, biochemistry and molecular biology at the Miller School. Dr. Kenyon was vice provost for innovation at the University of Miami and chief innovation officer at the Miller School for 13 years. “Dr. Ali and colleagues have not only proven the value of their technology but have also demonstrated the grit and determination that is required to succeed.”
During his time at the Miller School, Dr. Ali’s approaches have redefined the drug discovery path for multiple programs across neuroscience, oncology and nephrology. His methodology has proven effective in his chosen focus, spinal cord injury, and well beyond. By fusing computational rigor, high-throughput experimentation and collaborative creativity, Dr. Ali is helping to turn scientific possibility into clinical reality.
Tags: ALS, amyotrophic lateral sclerosis, axon, cancer research, Dr. Alessia Fornoni, Dr. Hassan Ali, Dr. John Bixby, Dr. Jonathan H. Schatz, Dr. Norma Sue Kenyon, Dr. Vance Lemmon, Dr. Zane Zeier, drug discovery, entrepreneurship, neurological surgery, Peggy and Harold Katz Family Drug Discovery Center, spinal cord injuries, The Miami Project to Cure Paralysis, therapeutic targets