Indications

Inherited retina degeneration like Retinitis Pigmentosa (RP), Leber's congenital amaurosis (LCA) and Stargardt's disease (STGD) lead to severe vision impairment or blindness. Each indication is characterized by a different age of disease onset and speed of degeneration.

Disease Mechanism

A newly discovered cell death mechanism shows that photoreceptor cells degenerate and eventually die due to excessive cGMP signaling. This principal disease mechanism is caused by a large number of mutations in over 280 genes.

Patient numbers

Retinitis Pigmentosa (RP), Leber congenital amaurosis (LCA) and Stargardt disease (STGD) are each orphan diseases with a combined patient number of about half a million in Europe, North America and Japan.

TWO main challenges for establishing therapies

1. The blood-retinal barrier, shielding the retina and its photoreceptors from pathogens, toxins, etc., but which also prevents access for therapeutic compounds.

2. The enormous genetic diversity of hereditary retinal degeneration, which would in principle require establishing a new gene therapy for each individual gene mutation.

Two major innovations introduced by mireca

1. Mireca applies proprietary drug delivery technologies for sustained release of therapeutic compounds to the eye.

2. Mireca introduces cGMP analogues as a new class of therapeutic compounds that can interfere with excessive cGMP-signaling in photoreceptors. Importantly, excessive cGMP signaling is a phenomenon common to many, if not most, forms of hereditary retinal degeneration, thus allowing to treat many of these diseases with the same therapeutic compound.

Reading List

Wang T et al.: Two pathways of rod photoreceptor cell death induced by elevated cGMP, Hum Mol Genet., 26(12):2299-2306, 2017

Sothilingam V et al.: Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype, Hum Mol Genet., 24(19):5486-99, 2015

Arango-Gonzalez B et al.: Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration, PLoS One., 9(11):e112142, 2014

Xu J et al.: cGMP accumulation causes photoreceptor degeneration in CNG channel deficiency: evidence of cGMP cytotoxicity independently of enhanced CNG channel function., J Neurosci., 33(37):14939-48, 2013

Sahaboglu A et al.: Retinitis pigmentosa: rapid neurodegeneration is governed by slow cell death mechanisms, F. Cell Death Dis., 4:e488, 2013

Schlossmann J, Schinner E: cGMP becomes a drug target, Naunyn Schmiedebergs Arch Pharmacol., 385(3):243-52, 2012

Trifunović D et al.: Neuroprotective strategies for the treatment of inherited photoreceptor degeneration, Curr Mol Med., 12(5):598-612, 2012

Paquet-Durand F et al.: A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa, Hum Mol Genet., 20(5):941-7, 2011

Paquet-Durand F et al.: PKG activity causes photoreceptor cell death in two retinitis pigmentosa models, J Neurochem., 108(3):796-810, 2009

Farber DB, Lolley RN: Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina, Science, 186(4162):449-51, 1974

Scientific Output

Tolone A et al.: The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration, Int. J. Mol. Sci., 24(20):15277, 2023

Roy A et al.: Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration, Cell Death Discovery, 8(1):93, 2022

Power M et al.: Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP, Progress in Retinal and Eye Research, 74:100772, 2020

Himawan E et al.: Drug delivery to retinal photoreceptors, Drug Discovery Today, 24(8):1637-1643, 2019

Fischer DM et al.: Development of cGMP Analogues for the Pharmacological Treatment of Neurodegenerative Diseases of the Retina, Klinische Monatsblätter für Augenheilkunde, 236(3):253-260, 2019

Vighi E et al.: Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration, PNAS, 115 (13) E2997-E3006, 2018

Vighi E et al.: New cGMP analogues restrain proliferation and migration of melanoma cells, Oncotarget, 9(4):5301-5320, 2018

Hoffmann D. et al.: New dimeric cGMP analogues reduce proliferation in three colon cancer cell lines, European Journal of Medicinal Chemistry, 141:61-72, 2017

INtellectual property

PCT/EP2016/055659, Targeted liposomal delivery of cGMP analogues

PCT/EP2017/066113, PKG antagonists (Inhibitors)

PCT/EP2017/071859, PKG agonists (Activators)

PCT/EP2022/074740, Improved methods for production of cGMP analogs

ODD EU/3/15/1462, DF003 for Retinitis Pigmentosa

More unpublished patent applications