Researchers from the Department of Neurology and the Department of Chemistry and Biochemistry at UCLA have developed a novel ERβ ligand prodrug that is structurally designed to confer neuroprotection in neurodegenerative conditions (multiple sclerosis, Alzheimer’s disease, and cognitive deficits of menopause in otherwise healthy women).
BACKGROUND:
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination as well as axonal and synaptic loss in the central nervous system. Current MS treatments target immune cells and have immunomodulatory effects to reduce relapse rates, but they were designed to target brain cells to induce neural repair or improve in disabilities. Publications have shown that treatment with estrogens or estrogen receptor (ER) specific-ligands in the mouse model for MS (experimental autoimmune encephalomyelitis (EAE)) are neuroprotective as demonstrated by reduced disability, less cortical atrophy, increased remyelination and decreased glial activation and synaptic loss. Also, Phase 2 trials of treatment with a generic ER beta ligand in women with MS showed improved cognition, reduced cerebral cortex atrophy, and reduction of serum neurofilament light chain levels. The ERβ ligand used in preclinical studies was diarylpropionitrile (DPN), a generic ERβ ligand, and that used in human Phase 2 trials was estriol, a naturally occurring biologic. Neither of these treatments have patents based on novel chemistry.
INNOVATION:
Researchers at UCLA from the Department of Neurology and the Department of Chemistry and Biochemistry have developed a novel ERβ ligand prodrug that crosses the blood-brain barrier and confers neuroprotection similar to that of the highly efficacious DPN in mice and estriol in humans.
POTENTIAL APPLICATIONS:
- Monotherapy for multiple sclerosis
- Combination therapy for multiple sclerosis (added to a treatment targeting immune cells)
- Monotherapy for menopause related cognitive deficits in otherwise healthy women
- Monotherapy for Alzheimer’s disease
ADVANTAGES:
- High efficacy (Neuroprotective)
- Greater impact on permanent disabilities such as cognitive dysfunction, walking problems, balance problems, and other neurological deficits as compared to currently available drugs
- Minimal toxicity
- Minimizes off target effects of estrogen’s action on ER alpha in breast
DEVELOPMENT-TO-DATE:
In vivo testing on mouse model of MS (EAE) shows that concentrations of active drug were present in the central nervous system over multiple hours. The novel ERβ ligand prodrug was also shown to be effective in treating mice with EAE.
Related Papers (from the inventors only)
1-11
1. Meyer, C.E., et al. Neuroprotection in Cerebral Cortex Induced by the Pregnancy Hormone Estriol. Lab Invest 103, 100189 (2023).
2. Itoh, N., et al. Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice. Nat Commun 14, 6044 (2023).
3. Voskuhl, R., et al. Decreased neurofilament light chain levels in estriol-treated multiple sclerosis. Ann Clin Transl Neurol 9, 1316-1320 (2022).
4. Voskuhl, R.R., et al. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Natl Acad Sci U S A 116, 10130-10139 (2019).
5. MacKenzie-Graham, A., et al. Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry. Brain Behav 8, e01086 (2018).
6. Kim, R.Y., et al. Oestrogen receptor beta ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis. Brain 141, 132-147 (2018).
7. Itoh, N., et al. Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis. J Neuroimmunol 304, 63-71 (2017).
8. Voskuhl, R.R., et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 15, 35-46 (2016).
9. Wisdom, A.J., Cao, Y., Itoh, N., Spence, R.D. & Voskuhl, R.R. Estrogen receptor-beta ligand treatment after disease onset is neuroprotective in the multiple sclerosis model. J Neurosci Res 91, 901-908 (2013).
10. Ziehn, M.O., Avedisian, A.A., Dervin, S.M., O'Dell, T.J. & Voskuhl, R.R. Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. Lab Invest 92, 1234-1245 (2012).
11. Mackenzie-Graham, A.J., et al. Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis. J Neurosci Res 90, 1310-1323 (2012).