Targeting cholesterol homeostasis for therapy of demyelinating eye disease

Demyelinating eye diseases are a broad spectrum of pathologies affecting the optic nerve that can result in
irreversible loss of visual function. The majority has an autoimmune-inflammatory etiology, but some may result
from isolated inflammatory episodes or traumatic insult to the eye. Demyelination is also observed in eye
diseases not classically defined as demyelinating, like glaucoma, where it contributes to visual dysfunction.
The pathology typically initiates with immune-mediated oligodendrocyte (OL) cell death in the optic nerve.
This leads to myelin destruction followed by Wallerian degeneration of optic nerve axons and, eventually, retinal
ganglion cell (RGC) death. Available therapies are scarce and limited to immunosuppressants and anti-
inflammatory drugs that only reduce symptoms and delay disease progression. Neuroprotective and
neuroreparative therapies that prevent RGC degeneration and/or promote remyelination, and in turn preserve
visual function, are lacking. This is largely due to poor understanding of the underlying pathological processes
as well as repair mechanisms at play in these conditions.
Cholesterol is vital for proper development and functioning of the nervous system. It is essential for neurite
outgrowth, synaptogenesis, molecule trafficking across organelles and cells, intracellular signaling, myelination
and remyelination. Given the high demand of cholesterol for nervous system health, maintenance of optimal
cholesterol levels and homeostasis within the CNS is key and its disruption has been linked to neurological
disease such as Alzheimer’s, multiple sclerosis (MS) and traumatic brain injury (TBI). Importantly, alterations of
cholesterol homeostasis and metabolism have been described in demyelinating eye diseases, where RGCs and
OLs, which heavily rely on cholesterol for survival, axonal transmission, myelin formation and repair, are
disproportionally affected by damage. Remarkably, little has been done to address how maintenance of
cholesterol homeostasis within the visual system may favor neuroprotection and repair in demyelinating eye
disease, and filling this gap in knowledge may direct towards much needed new therapies.
Our overarching hypothesis is that restoring cholesterol homeostasis is therapeutic in demyelinating eye
disease. This will sustain neuroprotective and reparative remyelination mechanisms, whose failure is directly
responsible for irreversible loss of visual function in these pathologies. To investigate our hypothesis, we propose
two aims that will explore, with the experimental optic neuritis model in mice, two approaches to modulate
cholesterol homeostasis: 1) administration of the cholesterol carriers methyl-β-cyclodextrins (mβCDs) to
redistribute cholesterol within the demyelinated eye and provide it where needed for cell survival ad repair; 2)
inhibition of the sterol sensor TMEM97, both pharmacologically and with gene targeting strategies, in order to
favor neuroprotection and neurorepair.

Grant Number: 1R21EY037547-01
NIH Institute/Center: NIH
Principal Investigator: ROBERTA BRAMBILLA