New hope for MS

Multiple sclerosis, or MS, is a chronic autoimmune disease affecting more than 2.9 million people worldwide. It occurs when the immune system mistakenly attacks the myelin sheath, the protective insulation around nerve fibers, causing disruption of nerve signals between the brain and body. Symptoms can include numbness, tingling, vision loss, and paralysis.

While current treatments can reduce inflammation, no therapies yet exist to protect neurons or restore the damaged myelin sheath. Researchers have now taken a major step forward in the development of such a therapy, supported by funding from the National Multiple Sclerosis Society. They have identified two compounds that could remyelinate damaged axons.

Published in the journal Scientific Reports, the research, 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, or UIUC, was made possible through two National MS Society funding programs: a traditional investigator-initiated grant and the Society's Fast Forward commercial accelerator program.

"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.

Thanks to the funding, the researchers were able to launch a program that was licensed by Cadenza Bio, Inc. With subsequent investor financing, Cadenza Bio has supported continued development of the program. The company is now advancing toward clinical evaluation as a potential first-in-class therapy for people living with MS.

From discovery to development

The project builds on earlier research involving a compound called indazole chloride, known for promoting remyelination and modulating the immune system in mouse models of MS. While effective, indazole chloride lacked the pharmacological properties and patentability needed for clinical development and commercial investment, Tiwari-Woodruff said.

In collaboration with UIUC chemists Katzenellenbogen and Sung Hoon Kim, who synthesized the compounds, Tiwari-Woodruff's research group, led by recent UCR graduate Micah Feri, screened more than 60 indazole chloride analogs. This collaboration identified two lead candidates, K102 and K110, which exhibited improved safety, efficacy, and drug-like properties in both mouse models and human cells.

Of the two, K102 emerged as the lead compound. The researchers found it not only promotes remyelination but also modulates immune function, an important balance for MS therapies. It also showed promising results in human oligodendrocytes, the myelinating cells of the central nervous system, derived from induced pluripotent stem cells, suggesting the potential for translatability between the animal models and human disease.

Under normal conditions, oligodendrocyte precursor cells mature into myelin-producing oligodendrocytes to repair damaged myelin. In MS, however, this natural repair process often fails, leading to permanent nerve damage. Successful remyelination through a compound like K102 could restore faster nerve conduction and may help reduce long-term disability associated with the disease.

"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.

The title of the paper is "Chloroindazole based Estrogen Receptor β ligands with favorable pharmacokinetics promote functional remyelination and visual recovery."