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CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis
Daekwon Bae1,2, Ji-Young Lee3, Nina Ha4
1Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. bdg088@ckdpharm.com.
Abstract:
Despite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35-55 (MOG35-55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood-brain barrier (BBB) integrity. In MOG35-55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4-CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.
Insights
CKD-506, a novel HDAC6 inhibitor, shows therapeutic potential for multiple sclerosis (MS). It regulates immune responses and maintains blood-brain barrier integrity, offering a promising new treatment avenue for MS patients.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) therapies have limitations and adverse effects.
- There is a need for novel therapeutic strategies for MS.
Purpose of the Study:
- To evaluate the therapeutic potential of CKD-506, a selective HDAC6 inhibitor, in a mouse model of MS.
- To investigate the mechanisms underlying CKD-506's effects on immune responses and blood-brain barrier integrity.
Main Methods:
- Experimental autoimmune encephalitis (EAE) was induced in mice using MOG35-55.
- CKD-506 was administered under various treatment regimens (prophylactic, therapeutic, and switch from fingolimod).
- Immune cell proliferation, cytokine expression, blood-brain barrier integrity, and behavioral changes were assessed.
Main Results:
- CKD-506 demonstrated prophylactic and therapeutic effects in EAE mice.
- It reduced T cell proliferation and pro-inflammatory cytokine production (IFN-γ, IL-17A).
- CKD-506 preserved blood-brain barrier integrity and decreased immune cell infiltration in the spinal cord.
- Therapeutic efficacy was observed even after treatment discontinuation and showed no disease exacerbation when switching from fingolimod.
Conclusions:
- CKD-506 effectively modulates peripheral immune responses mediated by T cells and macrophages.
- CKD-506 strengthens blood-brain barrier integrity, crucial for MS treatment.
- CKD-506 represents a potential therapeutic agent for multiple sclerosis with promising efficacy and tolerability.
