Strategy for a potential Retinitis pigmentosa therapy. Model for the effects of the selective CNG channel modulator on rod and cone photoreceptors from wt-retina. Selective inhibition of rod CNG channels by means of cGMP analogs or channel pore blockers should delay rod photoreceptor degeneration and consequently protect cone functionality. This strategy will first be tested on heterologously expressed retinal CNG channels and then, in collaboration with F. Paquet-Durand and W. Haq (University of Tübingen), on retinal explant cultures and mouse models for this disease

Role of CNG channels in retinal degeneration

Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration that can cause complete blindness. Currently, there is no drug therapy for the approximately 2.5 million patients worldwide. RP is the result of multiple mutations in rod sensory cells causing elevated levels of cGMP. The aim of this study is to investigate an important target of cGMP toxicity: the cyclic nucleotide-gated (CNG) channels. cGMP leads to an increased opening probability of these ion channels and consequently to rod degeneration. Shortly thereafter, cone photoreceptor death occurs. The goal of this project is to identify and characterize selective modulators for the rod CNG channel isoforms that may allow slowing of disease development by targeted inhibition of these channels. The optimal modulators to be considered for a potential RP therapy should selectively inhibit rod CNG channels with high affinity and in this way preserve cone cell functionality.

Subject-related publications

Wucherpfennig, S., Haq, W., Popp, V., Kesh, S., Das, S., Melle, C., Rentsch, A., Schwede, F., Paquet-Durand, F., and Nache, V. (2022)
cGMP Analogues with Opposing Actions on CNG Channels Selectively Modulate Rod or Cone Photoreceptor Function.
Pharmaceutics 14, 2102.

Das, S., Popp, V., Power, M., Groeneveld, K., Yan, J., Melle, C., Rogerson, L., Achury, M., Schwede, F., Strasser, T., Euler, T., Paquet-Durand, F., and Nache V. (2022)

Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem.

Cell Death Dis., 13, 47.

Funding

Funding Institution: DFG
Project no. 437036164
Project leader: Nache Vasilica
Topic: "Targeting the rod cyclic nucleotide-gated (CNG) channels by means of novel cGMP-analogues: a mechanistic approach to prevent retinal degeneration."
Duration: Sept. 2020 - Aug. 2023

Cooperations

Prof. Dr. Francois Paquet-Durand

Cell Death Mechanisms Group, Institute for Ophthalmic Research, University of Tübingen

Dr. Wadood Haq

Neuroretinal Electrophysiology and Imaging Group, Institute for Ophthalmic Research, University of Tübingen

Dr. Frank Schwede

Biolog LSI, Bremen

Contact

Dr. Vasilica Nache

Phone: 03641 - 9 397668