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Updated: Nov 9, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Treatment with Non-specific HDAC Inhibitors Administered after Disease Onset does not Delay Evolution in a Mouse
Daniela Buonvicino1, Giuseppe Ranieri1, Alberto Chiarugi1
1Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Abstract:
Drugs able to efficiently counteract progression of multiple sclerosis (MS) are still an unmet need. Several lines of evidence indicate that histone deacetylase inhibitors (HDACi) are clinically-available epigenetic drugs that might be repurposed for immunosuppression in MS therapy. Here, we studied the effects of HDACi on disease evolution in myelin oligodendrocyte glycoprotein (MOG)-immunized NOD mice, an experimental model of progressive experimental autoimmune encephalomyelitis (PEAE). To obtain data of potential clinical relevance, the HDACi panobinostat, givinostat and entinostat were administered orally adopting a daily treatment protocol after disease onset. We report that the 3 drugs efficiently reduced in vitro lymphocyte proliferation in a dose-dependent manner. Notably, however, none of the drugs delayed evolution of PEAE or reduced lethality in NOD mice. In striking contrast with this, however, the lymphocyte proliferation response to MOG as well as Th1 and Th17 spinal cord infiltrates were significantly lower in animals exposed to the HDACi compared to those receiving vehicle. When put into a clinical context, for the first time data cast doubt on the relevance of HDACi to treatment of progressive MS (PMS). Also, our findings further indicate that, akin to PMS, neuropathogensis of PEAE in NOD mice becomes independent from autoimmunity, thereby corroborating the relevance of this model to experimental PMS research.
Insights
Histone deacetylase inhibitors (HDACi) did not prevent progressive experimental autoimmune encephalomyelitis in mice, despite reducing lymphocyte proliferation. These findings question the clinical relevance of HDACi for progressive multiple sclerosis (MS) treatment.
Area of Science:
- Neuroimmunology
- Epigenetics
- Pharmacology
Background:
- Multiple sclerosis (MS) lacks effective treatments for its progressive forms.
- Histone deacetylase inhibitors (HDACi) are epigenetic drugs with potential immunosuppressive properties for MS therapy.
Purpose of the Study:
- To investigate the efficacy of orally administered HDACi (panobinostat, givinostat, entinostat) in a mouse model of progressive experimental autoimmune encephalomyelitis (PEAE).
- To assess the impact of HDACi on disease progression, lethality, and immune responses in MOG-immunized NOD mice.
Main Methods:
- NOD mice were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce PEAE.
- Mice received daily oral administration of panobinostat, givinostat, or entinostat after disease onset.
- In vitro lymphocyte proliferation assays were performed.
- Disease evolution, lethality, MOG-specific lymphocyte proliferation, and spinal cord immune infiltrates (Th1, Th17) were analyzed.
Main Results:
- HDACi significantly reduced lymphocyte proliferation in vitro in a dose-dependent manner.
- None of the tested HDACi delayed PEAE progression or reduced mortality in NOD mice.
- However, HDACi treatment led to significantly lower MOG-specific lymphocyte proliferation and reduced Th1/Th17 spinal cord infiltrates compared to vehicle-treated controls.
Conclusions:
- The study casts doubt on the clinical relevance of HDACi for treating progressive multiple sclerosis (PMS).
- The findings suggest that neuropathogenesis in this PEAE model, similar to PMS, may become independent of autoimmunity.
- This model is corroborated as relevant for experimental PMS research.
