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Summary: Researchers have identified two compounds capable of repairing the protective myelin sheath damaged by multiple sclerosis, an important step toward reversing nerve injury rather than simply slowing it down. The lead compound, K102, not only promotes remyelination but also balances immune function, key to long-term neurological recovery.
In animal and cell studies, it restored myelin-producing cells and showed great potential for translation into human therapies. This discovery, which is now being developed by Cadenza Bio, could lead to the first therapy that helps regenerate, not just protect, nerve fibers in MS.
Key facts:
Myelin restoration: K102 and K110 promote myelin repair, and K102 emerges as the strongest candidate for MS treatment. Dual Action: K102 restores damaged axons while modulating immune function, a crucial balance for MS treatment. Toward clinical trials: Compounds are now moving toward human testing as part of a biotech-led translational program.
Source: UCR
Multiple sclerosis, or MS, is a chronic autoimmune disease that affects more than 2.9 million people worldwide.
It occurs when the immune system mistakenly attacks the myelin sheath, the protective insulation surrounding nerve fibers, causing disruption of nerve signals between the brain and body.
Symptoms may include numbness, tingling, vision loss, and paralysis.
While current treatments can reduce inflammation, there are still no therapies to protect neurons or restore damaged myelin sheath. Researchers have now taken a big step forward in developing 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, professor of biomedical sciences at the University of California, Riverside, School of Medicine, and John Katzenellenbogen, professor of chemistry at the University of Illinois Urbana-Champaign, or UIUC, was made possible by two funding programs from the National MS Society: a grant researcher-initiated tradition and the Society’s Fast Forward business accelerator. program.
“Our work represents more than a decade of collaboration, and the last four years have focused on identifying and optimizing new drug candidates that show great 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 licensed by Cadenza Bio, Inc. With subsequent funding from investors, Cadenza Bio has supported the continued development of the program.
The company is now moving toward clinical evaluation as a potential first-in-class therapy for people living with MS.
From discovery to development
The project builds on previous research involving a compound called indazole chloride, known to promote remyelination and modulate 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, analyzed more than 60 indazole chloride analogs.
This collaboration identified two lead candidates, K102 and K110, that exhibited increased safety, efficacy, and drug-like properties in both mouse models and human cells.
Of the two, K102 emerged as the lead compound. Researchers found that 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 possibility of translatability between animal models and human diseases.
Under normal conditions, oligodendrocyte precursor cells mature into myelin-producing oligodendrocytes to repair damaged myelin. However, in MS, this natural repair process often fails, causing permanent nerve damage.
Successful remyelination through a compound like K102 could restore faster nerve conduction and help reduce long-term disability associated with the disease.
“K110 is also a strong candidate,” Tiwari-Woodruff said. “It has slightly different effects on the central nervous system and may be better suited for other conditions like spinal cord injuries or traumatic brain injuries, so we’ll keep it in the works.”
From banking to biotechnology
Tiwari-Woodruff and Katzenellenbogen credit the National MS Society’s Fast Forward program with a game-changer. Fast Forward accelerates the commercialization of promising therapies by promoting partnerships between academia and industry.
The highly competitive grant allowed Tiwari-Woodruff and Katzenellenbogen to generate enough data to license Cadenza Bio to develop K102 and K110.
The patents are jointly owned 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 has always been to take a promising idea and turn it into a therapy that could help people with MS. We’re finally getting closer to that reality.”
Initially, the UCR Office of Technological Partnerships collaborated with the UIUC to seek patent protection. Grace Yee, deputy director of technology commercialization at UCR, said the joint efforts of UCR, UIUC and the National MS Society advocated and promoted the technology to investors and industry for business development.
“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,” he said.
“When investors expressed interest in the technology, UCR and UIUC helped them understand how the technology addresses an unmet need in the treatment of MS. These efforts led to the licensing agreement with Cadenza Bio.”
Elaine Hamm, chief operating officer of Cadenza Bio, said she and Carol Curtis, co-founder of Cadenza Bio, were impressed by the possibility of moving from slowing axonal damage to repairing it.
“This is the future we want to build,” Hamm said. “That’s why we licensed the technology and why we’re excited to bring it to patients who need it.”
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, he said, proved to be a pivotal decision.
“The support from UCR – from leadership to infrastructure – has been extraordinary,” Tiwari-Woodruff said.
“None of this would have been possible without that support. 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.”
Although the initial focus is MS, the team believes that 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 non-clinical studies necessary to support first-in-human clinical trials.
“We are hopeful that clinical trials can begin soon,” Tiwari-Woodruff said. “It’s been a long journey, but that’s what translational science is all about: turning discovery into real-world impact.”
Funding: The research was also funded in part by grants from the National Institutes of Health and Cadenza Bio.
Tiwari-Woodruff, Katzenellenbogen, Kim and Feri were joined in the investigation 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. García Castro of the UCR; Kendall W. Nettles and Jerome C. Nwachukwu of the Scripps Research Institute, Florida; and David E. Martin and Curtis of Cadenza Bio, Oklahoma.
Key questions answered:
A: They discovered two new drug candidates that can remyelinate damaged nerve fibers, potentially reversing the symptoms of multiple sclerosis.
A: Unlike existing medications that only reduce inflammation, K102 helps restore the myelin sheath while regulating immune activity.
A: The compounds are advancing through preclinical testing and are expected to follow human clinical trials as part of an ongoing development program.
About this research news on multiple sclerosis and neuropharmacology
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala – UCR
Image: Image is credited to Neuroscience News.
Original research: Open access.
“Chloroindazole-based estrogen receptor β ligands with favorable pharmacokinetics promote functional remyelination and visual recovery” by Seema Tiwari-Woodruff et al. Scientific Reports
Abstract
Chloroindazole-based estrogen receptor β ligands with favorable pharmacokinetics promote functional remyelination and visual recovery.
Multiple sclerosis (MS) is a chronic autoimmune, demyelinating and neurodegenerative disease that causes motor, visual and cognitive deficits.
While existing treatments can slow disease progression, they rarely restore lost neurological function or significantly improve quality of life.
Estrogen receptor β (ERβ) has emerged as a promising therapeutic target due to its ability to activate non-classical signaling pathways involved in neuroprotection, immune modulation, and remyelination.
In this study, two selective chloroindazole-based ERβ ligands, K102 and K110, were identified for their favorable pharmacokinetic profiles and performance in preclinical absorption, distribution, metabolism and elimination (ADME) screening.
These compounds demonstrated biological activity by promoting oligodendrocyte (OL) differentiation in primary mouse and human OL cultures.
In vivo, they enhanced axonal remyelination and improved functional electrophysiological outcomes in two MS mouse models: experimental autoimmune encephalomyelitis (EAE) and cuprizone diet-induced demyelination.
Furthermore, K102 and K110 modulated immune responses, supporting OL survival and contributing to motor and visual recovery in EAE mice.
These findings provide compelling preclinical evidence to advance K102 and K110 into clinical development.
By simultaneously targeting neurodegeneration and inflammation through ERβ-mediated signaling, these compounds offer a novel and potentially transformative approach to MS therapy.
