Abstract
Purpose :
Published research on the role of toxic soluble oligomers of misfolded β-amyloid (Aβ) in neurodegenerative disease grows dramatically. These oligomers are increasingly becoming recognized as potential causes of synaptic dysfunction and neurodegeneration in Alzheimer disease, glaucoma and dry age-related macular degeneration (AMD). GAL-101 (formerly MRZ-99030), a novel small molecule, selectively clears misfolded Aβ from neural tissues to prevent formation of neurotoxic Aβ oligomers and their consequent neurotoxicity. We explored MOA and neuroprotective effect of GAL-101 via topical administration in animal models of glaucoma and dry AMD. These experiments led us to hypothesize that peak delivery from a single administration might provide sustained therapeutic effects.
Methods :
Topical delivery was tested in cynomolgus monkeys. Neuroprotection was tested in glaucoma rat model with 6 weeks elevated IOP, effect on Aβ deposits tested in 6 months CFH-/-and in 24 months old C57/6 mice with extensive Aβ deposits. Aβ toxicity was tested on hippocampal slices in vitromeasured via LTP.
Results :
GAL-101 affinity to Aβ measured by SPR is 30 nanomolar (nM), and showed rapid formation of amorphous, non-toxic aggregates of Aβ (”blobs”) seen on AFM. Single eyedrops in monkeys sustained GAL-101 concentrations >100 nM in the retina for >2 hours, via the sclera and choroid. RGC death in rats was 20% after 6 weeks IOP elevation, but <1% with daily GAL-101 eye drops (>90% neuroprotection), with similar results from single administration of GAL-101 via intravitreal or subcutaneous injection prior to IOP elevation. GAL-101 eye drops given in AMD mice the first 3 of each 30 days resulted in 40-60% less toxic Aβ deposits vs placebo after 90 days. 50 nM Aβ was toxic to hippocampal cells but was neutralized 20 minutes following addition of GAL-101. Following serial dilutions, a solution with GAL-101 < 0.1 nM but containing “blobs” still detoxified a fresh 50 nM Aβ solution.
Conclusions :
These results suggest that when a transient GAL-101 peak exceeds a threshold in a toxic Aβ solution it triggers a sustained detoxification, apparently facilitated by the “blobs”. Thus, a single administration delivering retinal peak levels of GAL-101 above threshold for <1 hour might have sustained detoxifying effect in dry AMD and glaucoma patients.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.