Breakthrough compounds may reverse nerve damage caused by multiple sclerosis

Although current treatments can help reduce inflammation, there are still no approved treatments that protect neurons or rebuild damaged myelin sheaths. Scientists have now made significant progress toward this 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 reportsled by Seema Tiwari Woodruff, professor of biomedical sciences at the University of California, Riverside, School of Medicine, and John Katzenelnbogen, professor of chemistry at the University of Illinois Urbana-Champaign (UIUC). The research was funded by two National MS Society initiatives: a record grant initiated by researchers and the organization’s Fast Forward program, which works to accelerate the commercialization of promising research.

“Our work represents more than a decade of collaboration, with the last four years focused on identifying and improving new drug candidates that show strong potential for treating MS and potentially other neurological diseases involving demyelination,” Tiwari Woodruff said.

With this support, the team launched a drug development program that has since been licensed to Cadenza Bio, Inc. Backed by investor funding, the company has continued to develop 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 previous studies involving a compound called indazole chloride, which has shown promise in promoting myelin repair and regulating immune responses in mouse models of multiple sclerosis. However, Tiwari-Woodruff explained that indazole chloride lacks the chemical properties and patentability required for clinical and commercial use.

Working with chemists Katzenellenbogen and Sung Hoon Kim, who created new versions of the molecule, the Tiwari-Woodruff group, led by recent UC Riverside graduate Mika Ferri, screened more than 60 analogues of indazole chloride. Through this effort, they identified two leading candidates, K102 and K110. Both showed safety, efficacy, and drug-like properties in tests in mice and human cells.

Of the two, K102 emerged as a prime candidate. Not only did it stimulate myelin repair, it also helped regulate immune activity, a crucial balance in MS treatments. The compound also performed well in human oligodendrocytes — cells responsible for producing myelin — derived from pluripotent stem cells, suggesting that the findings could effectively translate from animal studies to human diseases.

Normally, oligodendrocyte progenitor cells develop into mature myelin-producing cells that repair neuronal insulation. In MS, this repair process is often disrupted, leading to permanent nerve damage. A compound like K102 that can restore myelin can help improve nerve signal transmission and possibly limit long-term disability.

“K110 is also a strong candidate,” Tiwari Woodruff said. “It has slightly different effects on the central nervous system and may be more appropriate for other conditions such as spinal cord injury or traumatic brain injury, so we are keeping it in the pipeline.”

From bench to biotechnology

Tiwari Woodruff and Katzenelnbogen consider the National Multiple Sclerosis Society’s Fast Forward program a turning point. Fast Forward accelerates the commercialization of promising therapies by strengthening industry-academic partnerships. The highly competitive grant enabled Tiwari-Woodruff and Katzenellenbogen to generate enough data to license the rights to Cadenza Bio to develop K102 and K110. The patents are held jointly by the UCR and UIUC, with an exclusive global licensing agreement between the universities and Cadenza Bio.

“This project was a good example of how long-term academic collaboration can lead to real-world applications,” Katzenelnbogen said. “Our shared goal has always been to take a promising idea and develop it into a treatment that can help people with MS. We are finally one step closer to that reality.”

Initially, UCR’s Office of Technology Partnerships collaborated with UIUC to obtain patent protection. Joint efforts by UCR, UIUC and the National MS Society have championed and promoted the technology to investors and industry for commercial development, said Grace Yee, associate director of technology commercialization at UCR.

“Our resident entrepreneurs also helped advise the project, so the team was able to develop materials and messaging to highlight the business value of the project,” she said. “When investors expressed interest in the technology, UCR and UIUC helped them understand how the technology could address unmet needs in MS treatment. These efforts led to a licensing agreement with Cadenza Bio.”

Eileen Hamm, COO of Cadenza Bio, said she and Carol Curtis, co-founder of Cadenza Bio, were impressed by the potential to go from slowing axon damage to repairing axon damage.

“This is the future we want to build,” Hamm said. “That’s why we licensed the technology, and why we’re excited to take it to patients in need.”

More than a decade in the making

Tiwari Woodruff and Katzenelnbogen have worked together for over 12 years. Tiwari Woodruff’s transfer from UCLA to UCLA in 2014 was a pivotal decision, she said.

“The support from UCR – from leadership to infrastructure – has been exceptional,” said Tiwari Woodruff. “None of this would be possible without this support. Funding academic laboratories like mine and John’s is critical. This is dedicated work, driven by a deep love of science and commitment to human health.”

Although the initial focus is MS, the team believes K102 and K110 could eventually be applied to other diseases that involve nerve cell damage, including stroke and neurodegeneration.

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

“We hope that clinical trials will begin soon,” Tiwari Woodruff said. “It’s been a long journey – but that’s what translational science is about: turning discovery into real-world impact.”

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

Tiwari Woodruff, Katzenelnbogen, Kim, and Ferri were joined in the research by Flavio de Cárdenas, Alyssa M. Anderson, Brandon T. Paul, Devang Deshpande, Shane Desfor, Kelly C. Atkinson, Stephanie R. Peterson, Moynoloa T. Ajayi, Fernando Beltran, Julio Tapia, and Martin A. Garcia Castro of UCR; Kendall W. Nettles and Jerome C. Nwachukwu of the Scripps Research Institute in Florida; and David E. Martin and Curtis are from Cadenza Pew, Oklahoma.