MRZ-99030 - a novel modulator of β-amyloid (Aβ) aggregation for the topical neuroprotective treatment of glaucoma and age-related macular degeneration (AMD)

Abstract

Purpose: Recent evidence indicates that therapeutic approaches which reduce or normalize pathological changes in Aβ metabolism / aggregation could represent a promising neuroprotective strategy for the treatment of both dry AMD and glaucoma. AβSee Pharmaceuticals is developing topical MRZ-99030 - (R)-(2-[2-Amino-3-(1H-indol-3-yl)-propionylamino]-2-methyl-propionic acid) - for the treatment of glaucoma and AMD.

Methods: Surface plasmon resonance (SPR), dynamic light scattering (DLS), atomic force microscopy (AFM), CD-spectroscopy, SDS PAGE, Western blots / silver stains, fluorescence resonance energy transfer (FRET), transmission electron microscopy (TEM), thioflavin-T staining, long term potentiation (LTP) and patch clamp.

Results: The affinity of MRZ-99030 binding to Aβ_1-42 was determined to be 30 nM as demonstrated by SPR measurements. The combined interpretation of extensive results from experiments using the techniques listed above revealed that MRZ-99030 does not prevent direct protein / protein interactions between monomeric Aβ species, but rather promotes the formation of large, amorphous, globular Aβ species when present at a 10:1 stoichiometric excess to Aβ. Since amyloidogenic fibrillar structures are ultimately also not formed - as revealed by TEM and Thioflavin-T staining - MRZ-99030 is believed to trigger a non-amyloidogenic self-propagating / detoxifying pathway and thereby reduces the amount of intermediate toxic soluble oligomeric Aβ species. On a functional level, these findings are supported by electrophysiological experiments. LTP is regarded as electrophysiological correlate of neuronal synaptic function and is impaired by acute administration of Aβ oligomers. Co-incubation of Aβ with MRZ-99030 fully reversed deficits in LTP induced by Aβ_1-42 oligomers. Further, application of Aβ_1-42 was able to depolarize the membrane potential of cultured retinal ganglion cells (RGCs), an effect which was attenuated by co-incubation of Aβ with MRZ-99030.

Conclusions: MRZ-99030 is a modulator of Aβ aggregation which prevents the formation of soluble toxic oligomeric Aβ species. Topical MRZ-99030 was also effective in animal disease models of glaucoma and AMD. Phase I trials are almost completed revealing a favourable safety profile and a phase II clinical program is presently being planned.

Keywords: 412 age-related macular degeneration • 531 ganglion cells • 615 neuroprotection