A multidisciplinary USC research team has identified new compounds that may target a key driver of brain inflammation linked to Alzheimer’s disease. Their research just published in the Nature publication npj Drug Discovery.

The driver is an enzyme called “calcium-dependent phospholipase A2,” or cPLA2. The team discovered its role in brain inflammation by studying people who carry the APOE4 gene — the strongest genetic risk factor for Alzheimer’s disease. While many people who have the APOE4 gene don’t develop the disease, those with elevated levels of cPLA2 generally do.

• RELATED: Read more about the team’s path to discovery.

The problem is that cPLA2 is also essential for normal brain function, so any potential drug molecule would need to inhibit the enzyme’s activity without eliminating it. The molecular candidate would also need to be small enough to cross the blood brain barrier to be effective.

“In this study, we identified compounds that act selectively on cPLA2, with minimal effects on related PLA2 enzymes that are important for normal cellular function,” said senior author Hussein Yassine, director of the Center for Personalized Brain Health at the Keck School of Medicine of USC. “Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems.”

Alzheimer’s-linked brain inflammation: Evaluating molecules

Using large-scale computational screening, the team evaluated billions of potential molecules, prioritizing those predicted to be selective, brain-penetrant and active under biologically relevant conditions. Vsevolod “Seva” Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience developed the screening methods.

Once the team identified the top candidates, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences led the effort to formulate those compounds for administration in animal models and test their levels in the brain.

A cPLA2 inhibitor that reduced pathological cPLA2 activation in human brain cells exposed to Alzheimer’s-related stressors became the prime candidate.

In mouse models, the inhibitor penetrated the blood-brain barrier and modulated neuroinflammatory pathways. The study suggests that inhibiting cPLA2 could be a promising therapeutic approach for neurodegenerative diseases.

“Our goal is to find out whether targeting inflammation can alter Alzheimer’s risk — particularly in APOE4 carriers,” Yassine said. “This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease.”

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In addition to Yassine, Louie and Katritch, the study was led by co-first authors Anastasiia V. Sadybekov, Marlon Vincent Duro and Shaowei Wang, all of USC. Other authors include Brandon Ebright, Dante Dikeman, Cristelle Hugo, Bilal Ersen Kerman, Qiu-Lan Ma, Antonina L. Nazarova, Arman A. Sadybekov and Isaac Asante, all of USC.

The research was supported with grants from the National Institute on Aging (U01AG094622, RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530); the National Institute of General Medical Sciences (R01GM147537); Department of Defense (W81XWH2110740), the Alzheimer’s Drug Discovery Foundation (GC-201711–2014197); USC CTSI KL2 (UL1 TR000004); and donations from the Vranos and Tiny Foundations and Lynne Nauss.

Yassine, Katritch and Louie are the founders of PeBRx, which is developing cPLA2 inhibitors. No other authors have any competing interests.

Before married couple Barbara and Glenn Nakahara, both 87, started using hearing aids in 2023, they felt the effects of hearing loss in every aspect of their lives.

“We couldn’t understand what our doctors were saying, and telephone calls were hard,” Barbara Nakahara says. “When you can’t hear something on television or a movie with your family, you really miss a lot.”

The Nakaharas’ experience is typical for those who experience hearing loss and find it increasingly hard to engage with the world around them.

“Hearing loss not only impacts hearing and communication, but also a patient’s relationships, work life and independence,” says Janet Choi, assistant professor of Clinical Otolaryngology – Head and Neck Surgery at the Keck School of Medicine of USC.

Choi is the lead researcher on a new study from the USC Caruso Department of Otolaryngology – Head & Neck Surgery that is the first to link hearing devices, including hearing aids and cochlear implants, to improved social well-being among adults with hearing loss.

“Through the research, I really wanted to understand whether treating hearing loss using hearing aids or via cochlear implantation can have a positive impact on patients’ social lives,” Choi says.

The study, published in JAMA Otolaryngology – Head & Neck Surgery, showed that hearing aids and cochlear implants can improve social engagement and reduce isolation among adults with hearing loss. The research team did a systematic review of 65 studies covering more than 5,000 participants.

Researchers found that hearing devices help people feel more socially connected, more involved in conversations and less lonely. This research follows a January 2024 study by Choi, which showed that adults with hearing loss who use hearing aids have an almost 25% lower risk of mortality. Both studies and other research suggest that treating hearing loss can improve both lifespan and social quality of life.

“Ultimately, our goal as physicians is to have happier, healthier patients,” says Professor John Oghalai, department chair of otolaryngology – head and neck surgery and Leon J. Tiber and David S. Alpert Chair in Medicine at Keck School of Medicine. “This research is really getting to the outcome of helping people be happier, and that’s a direct correlation with our goal of taking care of patients.”

The Nakaharas began to seriously consider hearing devices after Glenn Nakahara’s brother shared that their father had spent his later years socially isolated due to his hearing challenges.

“Glenn’s parents were engaged [with other people] all their lives; people came to visit or they went out to dinner,” Barbara Nakahara says. “To learn that Harry [Glenn’s father] was just sitting there was a really upsetting moment.”

The Nakaharas, already patients at Keck Medicine of USC, then met with audiologist Nicole Greene, who guided them through the process of selecting the best hearing devices for their situation.

Fighting stigma

While the Nakaharas were eager to seek treatment, Choi says that young patients experiencing hearing challenges tend to put up the greatest resistance to using hearing devices.

“There’s a huge social stigma linked to hearing loss and using hearing aids in our society; people think that they make them look old,” Choi says. “As a result, a lot of people are in denial.”

Choi wanted to challenge that stigma because of her personal connection to hearing loss. She was born without a left ear canal due to a congenital condition called aural atresia. A childhood surgery failed to fix the problem completely, so she had to rely almost entirely on her right ear. Although Choi’s pediatrician recommended hearing aids early on, her parents worried that she would be picked on by her classmates.

She didn’t start using hearing aids until a physician who Choi trained with at the University of Minnesota advised that she could be missing crucial words — especially in the operating room, where competing sounds could lead to confusion.

“Hearing aids actually made a huge, positive impact for me, especially in work environments,” Choi says. “I didn’t miss words anymore.”

Relating to patients

Choi’s experience helps her relate to patients with hearing loss — especially those who are newly diagnosed.

“I really like showing my hearing aids to my patients, because they usually don’t even notice that I’m wearing them,” says Choi, who noted that the diversity of options for hearing devices has expanded widely in the last 10 to 20 years. Most patients first think of the bulky, highly visible hearing aids of the past when faced with the reality of hearing loss, but many devices are now smaller, compact and less visible — if patients even want to conceal them.

“I personally advocate for hearing aids as a positive tool to celebrate and embrace,” Choi says. “They can even be a fashion statement at some point.”

Easing access for others

While hearing devices offer a relatively quick source of relief for many patients with hearing loss, finding the best device can be daunting. Choi’s difficulty navigating the hearing loss landscape as a patient — even while working in that field — was an eye-opening experience.

Choi says she had to try different hearing-aid molds and materials before she found the ones that worked for her. “Learning that process myself, I knew we had to do better,” she says. “That’s why I got into hearing-loss research — to understand what treating hearing loss can do and then make it more accessible for everyone.”

Since then, she has authored more than 50 publications in peer-reviewed journals and book chapters and presented at national and international conferences. Her research projects include population-based studies examining the impact of hearing loss and its treatment on health outcomes, as well as the development of artificial intelligence-based solutions to ease access to hearing care.

Reaching across disciplines

Before her fellowship in otology, neurotology and lateral skull base surgery at the University of Minnesota, Choi completed a five-year otolaryngology residency at Keck School of Medicine. She returned to USC as a faculty member and practitioner in 2023, crediting the collaborative nature of her department and USC as an institution as the reason for her return to the university.

“It was the people,” Choi says. “I enjoy working in a very collegial environment, where a lot of collaboration happens not just in my department, but as a whole. USC as an institution, especially for my research, is very multidisciplinary — I have a lot of collaborators in disciplines such as gerontology and neurology.”

“At USC, faculty in different departments want to work together to solve difficult problems and develop innovative ideas,” Oghalai adds. “Our goal is not just to provide medical care, but to advance medical care. And we do that through collaboration and innovation.”

Oghalai hopes Choi’s new research has her desired effect of expanding understanding of the benefits of treating hearing loss.

“My hope is that this research cues people into the idea that [hearing devices] can actually help you accomplish more in your life, and not detract from your life,” he says.

Parsing through the social benefits

Before Choi’s breakthrough finding, many studies already showed that hearing loss is connected to negative social engagement and loneliness. What wasn’t known was whether treating hearing loss with hearing aids or cochlear implantation could have a positive impact on social well-being. For the study, her team reviewed findings from the previous studies and found there was a “really significant, positive impact for both hearing-aid use and cochlear implantation in multiple domains of social outcomes,” Choi says.

Those with cochlear implants reported the biggest improvements in social quality of life, likely because the implants provide greater hearing restoration than hearing aids, especially for people with severe hearing loss. The researchers also found that individuals using hearing devices felt more socially connected and less limited and anxious in social situations.

Like the participants from the study, Choi and the Nakaharas saw their social experiences enriched after treating their hearing loss.

Before using hearing devices, Choi would smile and nod or laugh at a joke without fully understanding when someone spoke to her on her left side.

“That’s something that a lot of people with hearing loss actually do, because it’s cumbersome to have to ask others to repeat themselves constantly,” she said. “You have to pretend in a lot of situations.”

For the Nakaharas, treating their hearing loss meant fully experiencing their granddaughters’ volleyball games for the first time and the promise of better engagement with the girls as they age into college. “At our age you have to enjoy all of this, because we’re not going to be around forever,” Barbara Nakahara says.

“The hearing aids are a very big plus because we can continue to watch them grow happily,” Glenn Nakahara adds.

Ten years ago, two pediatric heart specialists approached USC biomedical engineer Gerald Loeb with an idea for a new pacemaker designed for babies, whose hearts are too small for conventional models.

The tiny device wouldn’t require open-chest surgery, sit inside the heart or have wire leads, which often break. Inserted under the breastbone through a small tube, the miniature pacemaker — a little bigger than a vitamin E capsule — would fit securely between the heart and its surrounding pericardial membrane.

Loeb is no stranger to medical innovation. A biomedical engineering professor at the USC Viterbi School of Engineering, Loeb developed and patented an artificial fingertip with a complete sense of touch that was licensed to a successful spin-off company from his USC lab. He specializes in electronic devices that connect with the nervous system.

“My career consists of people coming in with crazy ideas and deciding which ones are practical enough to give a shot,” Loeb says.

The pericardial micro pacemaker is getting its shot. He and Yaniv Bar-Cohen, a pediatric heart specialist at the Keck School of Medicine of USC and Children’s Hospital Los Angeles, developed, patented and successfully demonstrated a working model. Bar-Cohen is in talks with pacemaker companies that can bring their device to market. They envision it being used in babies, children and adults.

From pill-sized pacemakers to stem cell therapies and new cancer treatments, USC researchers are collaborating to advance medical innovations, address complex health challenges and improve lives. Trojan researchers across the sciences are seeking to cure blindness, develop new testing options for cancers such as ovarian and breast cancers, and delay the onset of arthritis. They are also finding new ways to detect and slow the progression of Alzheimer’s disease.

“At USC, we don’t just imagine the future of medicine; we engineer it, we patent it, we launch it,” says Ishwar K. Puri, USC’s senior vice president of research and innovation. “Our researchers are redefining what’s possible. This is what it means to innovate like a Trojan.”

The USC Stevens Center for Innovation plays a pivotal role in many of these efforts, managing the intellectual property generated from more than $1.2 billion in annual research funding across medicine, engineering and the sciences — a scale that reflects USC’s growing influence in shaping the future of health technologies.

“We’re seeing more faculty startups launch with strong science and real commercial potential,” says Erin Overstreet, executive director at the Stevens Center. “We want to make sure we’re helping them build the right foundation — from patents to partnerships.”

A long lead

The path from discovery in the lab to the marketplace is painstakingly slow. Each promising treatment must go through rigorous scientific review before it can advance to clinical trial and eventually to FDA review and approval. According to some estimates, the cost of producing a single FDA-approved drug ranges from $1 billion to $3 billion over a 10- to 15-year period. The odds of success are slim: Only 3%, give or take, win FDA approval.

USC scientists are on the front line of finding ways to accelerate discovery and compress the timeline. They are launching startups to inspire investment and working closely with private industry.

USC’s Vsevolod “Seva” Katritch is using AI and computational methods to screen billions of compounds to disrupt the earliest — and most time-consuming — phase of drug discovery: the identification of “hits” and development of “leads.” He and Charles McKenna, professor of chemistry and pharmaceutical sciences, host workshops to encourage AI drug discovery. Annie Wong- Beringer, associate dean for research at the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, is using organon- a-chip technology (where cells from specific organs, such as the heart, are grown on silicone wafers) to screen potential drugs for issues such as liver toxicity earlier in the process.

“USC is not only publishing discoveries but actively developing therapies and spinning out biotech companies,” says Steve Kay, who directs the USC Michelson Center for Convergent Bioscience and is the co-director of the USC Norris Center for Cancer Drug Development. “We’re building an ecosystem that turns basic science into treatments — especially for diseases affecting our local population, like pancreatic cancer, leukemia and Alzheimer’s.”

“Historically, universities stopped at publishing discovery research — insights into pathways, cell types, animal models — while pharma took it from there,” continues Kay, a University and Provost Professor of Neurology, Biomedical Engineering and Quantitative and Computational Biology. “What we’re doing now is moving our discoveries further along the commercialization path before handing them off. That means more value retained at USC and more ownership for inventors.”

Here’s a sample of USC-licensed startups, drugs and devices:

• Be Biopharma has licensed technology developed by microbiologist and Keck School of Medicine Distinguished Professor Paula Cannon to edit the genes of the body’s own B cells to express therapeutic antibodies for indications including cancer, autoimmune disease, infectious disease and central nervous system applications.
• AcuraStem, a startup co-founded by Justin Ichida, is developing drugs to treat ALS and frontotemporal dementia. In late 2023, AcuraStem signed an exclusive licensing agreement with pharmaceutical giant Takeda to bring the discoveries to market.
• Synchronicity Pharma, a biotech startup co-founded by Steve Kay, has completed early safety trials in humans for a compound that selectively attacks glioblastoma — a deadly form of brain cancer — stem cells. The compound, SHP1705, targets the circadian clock proteins hijacked by glioblastoma stem cells, impairing the cancer cells’ ability to survive and grow. Circadian clock proteins regulate the body’s sleep-wake cycle and other daily rhythms.
• Plurocart, a startup founded by Denis Evseenko at Keck School of Medicine, is developing a “regenerative pouch” to replace cartilage that’s been damaged by a fall, sports injury or other trauma. The pouch contains hundreds of thousands of young cartilage cells derived from stem cells. “It’s a little reparative structure that you can surgically deliver right into the cartilage defect,” Evseenko says.

 

Interdisciplinary Breakthroughs

The famed inventor Nikola Tesla is believed to have said, “Be alone — that is the secret to invention.”

For Trojan inventors like Charles Liu, the opposite is true: Their secret to invention is to work as a team. Even though the process may take years, licensure does not dim Liu’s enthusiasm for helping patients recover function from brain injuries or diseases.

Co-founder of USC’s Neurorestoration Center and professor of clinical neurological surgery, urology and surgery at the Keck School of Medicine, Liu specializes in the creation of implantable devices that respond in real time to abnormal brain activity. His prosthetics for the brain are designed to help patients who suffer from brain conditions such as epilepsy, Parkinson’s disease, memory loss and more.

Through a combination of engineering and medicine, he is a healer in the rapidly emerging field of biomedicine known as neuroprosthetics. “The hope is that neuroprosthetics will become an important tool for functional neurorestoration in human patients, which will work in synergy with other strategies such as regenerative medicine and neuromodulation-enhanced learning,” Liu says. “The hope is that all aspects of human neurological disabilities can be restored beyond what conventional healing and rehabilitation can achieve.”

Associate Professor of Neurological Surgery and of Biomedical Engineering at the USC Viterbi School of Engineering Dong Song, who often collaborates with Liu, focuses on addressing brain health issues through engineering.

For instance, he is working on a brain prosthesis to restore episodic memory in patients who suffer from memory-impairing conditions such as neurological disease or injuries.

Using a computational model, his team records neural signals from one part of the hippocampus and stimulates another to rebuild broken memory pathways by using implantable brain devices.

“Within the next five to 10 years, our goal is for this device to transition from proof-of-concept studies to broader clinical trials, ultimately providing a therapeutic option for conditions like traumatic brain injury and early-stage Alzheimer’s disease,” Song says.

Getting to Yes

At USC, some scientists bring their early ideas to the Stevens Center, which helps turn rough prototypes into patented devices. That process often extends to launching a startup company where strong intellectual property can give investors the confidence to fund the testing and development needed to bring an invention to market.

In recent years, the center has refined the way it handles technology transfer — the process of moving university research into the real world. Since joining the center in January 2024, Overstreet has emphasized investing early in high-quality patent applications and being more selective about which inventions to pursue patent protections for.

“We don’t try to patent every idea that comes through our office,” she explains. “Instead, after a careful review, we move forward with patents on about two-thirds of the inventions we see. For those, we put in the work to draft applications that clearly define what makes the invention new and protectable. Strong patents not only stand up if challenged — they are also more attractive to companies and investors, making them far more licensable assets for USC and our inventors.”

The center’s licensing team now numbers more than 20 professionals who work closely with faculty to negotiate startup-friendly agreements. Many deals begin with low-cost, short-term options to reduce risk for early-stage companies. Later, they are upgraded to full licenses once funding is secured.

“Our job is to reduce friction,” Overstreet says. “We want to get to yes, and we want startups to succeed.”

The Stevens Center oversees licensing of all technologies at USC, including diagnostics and medical devices. Companies like CpG Diagnostics and Regenerative Patch Technologies (RPT) — co-founded by Mark Humayun of USC Viterbi, the USC Roski Eye Institute and Keck School of Medicine — are part of USC’s expanding innovation footprint. RPT developed an implantable retinal patch for restoring vision in people with age-related macular degeneration. It remains one of the university’s most cited examples of therapeutic success.

Recent studies, backed in part by the taxpayer-supported California Institute for Regenerative Medicine, indicate the patch appears regenerative, not just slowing the degenerative disease but also reversing its course. Clinical studies are underway.

Signals of Strength

As the life-sciences industry shifts toward personalized and cell-based therapies, Overstreet believes USC is better positioned than ever to rise among the top institutions for innovation. Recent deals with well-capitalized companies, such as Be Biopharma, reflect a maturing pipeline of faculty-led ventures — and illustrate an unrelenting determination that is a hallmark of USC research.

“These are signals of strength,” she says. “They show what’s possible when you combine groundbreaking research with strong intellectual property and the right partnerships.”

With more than $1.2 billion in annual research activity and a sharpened focus on translational outcomes, Trojan inventors are laying the groundwork for a future where USC discoveries save and improve more lives, faster than before.