Targeting the rod cyclic nucleotide-gated (CNG) channels by means of novel cGMP-analogues: a mechanistic approach to prevent retinal degeneration.

• Applicant: Dr. Vasilica Nache
• Subject Area: Anatomy and Physiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437036164

Mutations in different genes expressed in rod photoreceptors trigger an inherited degenerative disease of photoreceptors, known as “retinitis pigmentosa (RP)”. This disease leads typically to severe impairment of vision and very often to blindness. To date there is still no cure for RP-patients. The initial steps of the RP development are associated with increased cGMP levels in the diseased photoreceptors. However, the pathway by which the cGMP-concentration imbalance leads to photoreceptor death is still unclear. The purpose of this study is to examine one important target of cGMP toxicity: the cyclic nucleotide-gated (CNG) ion channels. While in the healthy photoreceptor, in the absence of light stimuli, the intracellular free cGMP triggers only approximately 3% CNG-channel activation, under RP-conditions, the pathological [cGMP] induces exacerbated activation of the CNG channels. The subsequent increased Ca2+-influx leads through a still unknown mechanism to the degeneration first of the rods photoreceptors followed shortly after by the death of the cone photoreceptors. By means of novel cGMP-analogues, we propose a pharmacological approach to slow down or even stop the cascade of events leading to rod photoreceptor death, preserving in this way the cone cell function. Cyclic-nucleotide (CN) analogues have already shown their potential as promising drugs, for example, in cancer research or as additives to improve organ preservation for transplantation. The aim of this project is to identify the best cGMP-analogues candidates for a potential RP-therapy that inhibit selectively and with a high affinity the rod CNG channels only, i.e. without inhibiting, at the same time, the cone CNG channels. To achieve this, we will test first, already existent cGMP-analogues, and if necessary we will propose strategies for developing new compounds tailored to our needs.In addition, characterizing the effect of the respective cGMP-analogues on different CNG-channel isoforms represents the key for understanding how cyclic nucleotides bind to and activate the channels, as well as the structural features that underlie the ligand selectivity mechanism. This important piece of information represents the secondary aim of this project, and it will add to our knowledge regarding the molecular mechanism of CNG-channel activation. Our findings will be relevant not only for the CNG-channel field but for all scientists working on the family of CN-modulated ion channels which include beside the CNG-channel family, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and ether-à-go-go-type (KCNH) channels.This study has great potential to initiate or to further develop therapeutic strategies not only for RP-patients, but also for patients with Achromatopsia, a retinal disease triggered by cone degeneration.

• DFG Programme: Research Grants