Health

Breakthrough compounds may reverse nerve damage caused by multiple sclerosis

Multiple sclerosis (MS) is a long-term autoimmune condition that affects over 2.9 million people around the world. In MS, the immune system mistakenly attacks the myelin sheath, a protective layer that insulates nerve fibers. This damage interrupts communication between the brain and body, leading to symptoms such as numbness, tingling, vision problems, and paralysis.

Although existing treatments can help reduce inflammation, there are still no approved therapies that protect neurons or rebuild the damaged myelin sheath. Scientists have now made significant progress toward that goal with support from the National Multiple Sclerosis Society. Their work has led to the discovery of two compounds capable of promoting remyelination, the process of repairing the myelin coating on nerve fibers.

The study, published in Scientific Reports, was led by Seema Tiwari-Woodruff, a professor of biomedical sciences at the University of California, Riverside, School of Medicine, and John Katzenellenbogen, a professor of chemistry at the University of Illinois Urbana-Champaign (UIUC). The research was funded through two National MS Society initiatives: a standard investigator-initiated grant and the organization's Fast Forward program, which accelerates commercialization of promising research.

"Our work represents more than a decade of collaboration, with the last four years focused on identifying and optimizing new drug candidates that show strong potential to treat MS and possibly other neurological diseases involving demyelination," Tiwari-Woodruff said.

With this support, the team launched a drug development program that has since been licensed by Cadenza Bio, Inc. Backed by investor funding, the company has continued advancing the research and is preparing for clinical testing of what could become a first-of-its-kind treatment for people with MS.

From discovery to development

This new work builds on earlier studies involving a compound called indazole chloride, which had shown promise in promoting myelin repair and regulating immune responses in mouse models of MS. However, indazole chloride lacked the chemical properties and patent potential required for clinical and commercial use, Tiwari-Woodruff explained.

Working with UIUC chemists Katzenellenbogen and Sung Hoon Kim, who created new versions of the molecule, Tiwari-Woodruff's group, led by recent UC Riverside graduate Micah Feri, screened more than 60 analogs of indazole chloride. From this effort, they identified two standout candidates, K102 and K110. Both showed better safety, efficacy, and drug-like characteristics in tests using mice and human cells.

Among the two, K102 emerged as the leading candidate. It not only stimulated myelin repair but also helped regulate immune activity, a critical balance for MS therapies. The compound also performed well in human oligodendrocytes -- cells responsible for producing myelin -- derived from induced pluripotent stem cells, suggesting the results could translate effectively from animal studies to human disease.

Normally, oligodendrocyte precursor cells develop into mature myelin-producing cells that repair nerve insulation. In MS, this repair process often breaks down, leading to lasting nerve damage. A compound like K102 that can restore myelin could help improve nerve signal transmission and potentially limit long-term disability.

"K110 is also a strong candidate," Tiwari-Woodruff said. "It has slightly different central nervous system effects and may be better suited for other conditions like spinal cord injury or traumatic brain injury, so we're keeping it in the pipeline."

From bench to biotech

Tiwari-Woodruff and Katzenellenbogen credit the National MS Society's Fast Forward program as a turning point. Fast Forward accelerates the commercialization of promising therapies by promoting academic-industry partnerships. The highly competitive grant enabled Tiwari-Woodruff and Katzenellenbogen to generate sufficient data to license the rights to Cadenza Bio to develop K102 and K110. The patents are jointly held by UCR and UIUC, with an exclusive, worldwide licensing agreement in place between the universities and Cadenza Bio.

"This project has been a good example of how long-standing academic collaborations can lead to real-world applications," Katzenellenbogen said. "Our shared goal was always to take a promising idea and develop it into a therapy that could help people with MS. We're finally getting close to that reality."

Initially, UCR's Office of Technology Partnerships collaborated with UIUC to seek patent protection. Grace Yee, assistant director of technology commercialization at UCR, said the joint efforts of UCR, UIUC, and the National MS Society advocated for and promoted the technology to investors and industry for commercial development.

"Our entrepreneurs-in-residence also helped advise the project, so the team was able to develop materials and messaging to highlight the project's commercial value," she said. "When investors expressed interest in the technology, UCR and UIUC helped them understand how the technology addresses an unmet need in treating MS. These efforts led to the licensing agreement with Cadenza Bio."

Elaine Hamm, chief operating officer at Cadenza Bio, said she and Carol Curtis, cofounder of Cadenza Bio, were impressed by the possibility of moving from slowing axon damage to repairing axon damage.

"This is the future we want to build," Hamm said. "It is why we licensed the technology, and why we are excited to move it forward to patients in need."

More than a decade in the making

Tiwari-Woodruff and Katzenellenbogen have worked together for more than 12 years. Tiwari-Woodruff's move from UCLA to UCR in 2014, she said, turned out to be a pivotal decision.

"The support from UCR -- from leadership to infrastructure -- has been extraordinary," Tiwari-Woodruff said. "None of this would've been possible without that backing. Funding for academic labs like mine and John's is crucial. This is selfless work, driven by a deep love of science and commitment to human health."

Though the initial focus is MS, the team believes K102 and K110 could eventually be applied to other diseases involving neuronal damage, including stroke and neurodegeneration.

Cadenza Bio is now advancing K102 through the necessary non-clinical studies required to support first-in-human clinical trials.

"We're hopeful that clinical trials can begin soon," said Tiwari-Woodruff. "It's been a long journey -- but this is what translational science is all about: turning discovery into real-world impact."

The research was also supported in part by grants from the National Institutes of Health and Cadenza Bio.

Tiwari-Woodruff, Katzenellenbogen, Kim, and Feri were joined in the research by Flavio D. Cardenas, Alyssa M. Anderson, Brandon T. Poole, Devang Deshpande, Shane Desfor, Kelley C. Atkinson, Stephanie R. Peterson, Moyinoluwa T. Ajayi, Fernando Beltran, Julio Tapia, and Martin I. Garcia-Castro of UCR; Kendall W. Nettles and Jerome C. Nwachukwu of The Scripps Research Institute, Florida; and David E. Martin and Curtis of Cadenza Bio, Oklahoma.

When men drink, women and children pay the price

A new global review led by La Trobe University has revealed the often-overlooked damage caused by men’s alcohol consumption to women and children, urging immediate policy action in Australia and around the world to address these gender-related harms.

The study, titled "Harms to Women and Children from Men's Alcohol Use: An Evidence Review and Directions for Policy," draws together data from three recent systematic reviews that analyzed 78 academic papers.

Worldwide, as many as one in three women in some countries live with a partner who drinks heavily. Children in these households are also at greater risk of violence, neglect, poor health, and limited opportunities later in life.

These negative effects are especially severe in low- and middle-income nations and in places where gender inequality remains high.

The research, led by Professor Anne-Marie Laslett of La Trobe’s Centre for Alcohol Policy Research (CAPR) and published by the global nonprofit research organization RTI International, found that men typically consume alcohol more heavily than women and are more likely to harm others when they drink.

As a result, women and children bear a disproportionate share of the consequences, including physical injuries, emotional distress, economic strain, and disruptions to schooling and family life.

"Research shows that the consequences of men's alcohol use extend far beyond the individual that drinks," Professor Laslett said.

"Women and children pay a heavy price, yet policies rarely take their experiences into account. This is a major gap in international public health and social policy."

Global data further indicates major differences between countries in how much and how often men and women drink. In many regions, these disparities make the impact of men’s alcohol use on women and children even more severe.

"Globally there has been poor recognition that others' drinking, and particularly men's drinking, contributes to many harms to women and children," Professor Laslett said.

"Social, cultural and economic policies, as well as alcohol-specific policies, need to change to ensure that they are responding to the harms to women and children highlighted in this review."

In Australia, the findings are particularly timely given growing national attention to domestic and family violence.

Alcohol's role in driving partner violence has been recognised in recent government reviews, with calls to strengthen regulation and prevention strategies.

Australia's Federal Government last year commissioned a rapid review that recommended addressing alcohol's regulatory environment.

The review emphasizes that while proven policies such as raising alcohol taxes, restricting availability, and limiting marketing remain essential, they should be paired with interventions that tackle harmful gender norms and empower women and children.

An intersectoral approach involving health, legal and social services is critical for meaningful change.

Professor Siri Hettige, a researcher from Sri Lanka's University of Columbo who collaborated on the project, said targeted, community-level interventions that addressed the realities faced by women and children were essential.

"Given the nature of the social context in which the harm to women and children from men's drinking occurs, interventions to reduce such harms might have to go beyond current alcohol policies," Professor Hettige said.

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MIT’s “stealth” immune cells could change cancer treatment forever

Scientists have created a new and more advanced form of immune-based cancer therapy using engineered cells known as CAR-NK (natural killer) cells. Like CAR-T cells, these modified immune cells can be programmed to recognize and attack cancer, but they rely on a different type of immune cell that naturally targets abnormal or infected cells.

A team from MIT and Harvard Medical School has now developed a more effective way to engineer CAR-NK cells that dramatically reduces the chance of the body’s immune system rejecting them. Immune rejection has been one of the biggest limitations of cell-based therapies, often weakening their effectiveness.

This innovation could also make it possible to produce “off-the-shelf” CAR-NK treatments that are available immediately after diagnosis, rather than waiting weeks for custom-engineered cells. Traditional CAR-NK and CAR-T manufacturing methods typically require several weeks to complete before patients can begin treatment.

“This enables us to do one-step engineering of CAR-NK cells that can avoid rejection by host T cells and other immune cells. And, they kill cancer cells better and they’re safer,” says Jianzhu Chen, an MIT professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.

In tests using mice with humanized immune systems, the newly engineered cells successfully destroyed most cancer cells while avoiding attack from the host’s own immune defenses.

Rizwan Romee, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, is also a senior author of the paper, which was published in Nature Communications. The study’s lead author is Fuguo Liu, a postdoctoral researcher at the Koch Institute and a research fellow at Dana-Farber.

Evading the immune system

Natural killer (NK) cells are a vital part of the body’s built-in immune defense, responsible for identifying and destroying cancerous and virus-infected cells. They eliminate these threats through a process called degranulation, which releases a protein known as perforin. This protein punctures the membrane of target cells, leading to their death.

To produce CAR-NK cells for treatment, doctors typically collect a blood sample from the patient. NK cells are then extracted and engineered to express a specialized protein called a chimeric antigen receptor (CAR), which is designed to target specific markers found on cancer cells.

Once modified, the cells must multiply in the lab for several weeks before there are enough to be infused back into the patient. The same general process is used for CAR-T cell therapies, some of which have already been approved to treat blood cancers like lymphoma and leukemia. CAR-NK therapies, however, are still being tested in clinical trials.

Because growing enough personalized CAR-NK cells takes time and the patient’s cells may not always be healthy enough for reliable use, scientists have been exploring an alternative: creating NK cells from healthy donors. These donor-derived cells could be mass-produced and stored for rapid use. The challenge, however, is that the recipient’s immune system often identifies donor cells as foreign and destroys them before they can attack the cancer.

In their latest research, the MIT team aimed to solve this problem by helping NK cells “hide” from immune detection. Their experiments showed that removing surface proteins known as HLA class 1 molecules allowed NK cells to avoid attack from T cells in the host’s immune system. These proteins normally act as identity markers that tell the immune system whether a cell belongs to the body.

To make use of this insight, the researchers added a sequence of siRNA (short interfering RNA) that silences the genes responsible for producing HLA class 1 proteins. Along with this genetic tweak, they introduced the CAR gene itself and another gene that encodes either PD-L1 or single-chain HLA-E (SCE), both of which help strengthen the NK cells’ cancer-fighting abilities.

All of these genetic components were combined into a single DNA construct, which allowed the team to efficiently convert donor NK cells into immune-evasive CAR-NK cells. Using this method, they engineered cells that target CD-19, a protein commonly found on malignant B cells in lymphoma patients.

NK cells unleashed

The researchers tested these CAR-NK cells in mice with a human-like immune system. These mice were also injected with lymphoma cells.

Mice that received CAR-NK cells with the new construct maintained the NK cell population for at least three weeks, and the NK cells were able to nearly eliminate cancer in those mice. In mice that received either NK cells with no genetic modifications or NK cells with only the CAR gene, the host immune cells attacked the donor NK cells. In these mice, the NK cells died out within two weeks, and the cancer spread unchecked.

The researchers also found that these engineered CAR-NK cells were much less likely to induce cytokine release syndrome — a common side effect of immunotherapy treatments, which can cause life-threatening complications.

Because of CAR-NK cells’ potentially better safety profile, Chen anticipates that they could eventually be used in place of CAR-T cells. For any CAR-NK cells that are now in development to target lymphoma or other types of cancer, it should be possible to adapt them by adding the construct developed in this study, he says.

The researchers now hope to run a clinical trial of this approach, working with colleagues at Dana-Farber. They are also working with a local biotech company to test CAR-NK cells to treat lupus, an autoimmune disorder that causes the immune system to attack healthy tissues and organs.

The research was funded, in part, by Skyline Therapeutics, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund and the Elisa Rah Memorial Fund, the Claudia Adams Barr Foundation, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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Breakthrough compounds may reverse nerve damage caused by multiple sclerosis

When men drink, women and children pay the price

Report shows 'stark' gender gap in HIV prevention

MIT’s “stealth” immune cells could change cancer treatment forever

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