Overview

CLCN4-related neurodevelopmental condition (CLCN4-NDC) is one of the more recently discovered rare X-linked monogenic disorders. It is caused by inherited or de novo pathogenic variants of the CLCN4 gene. It affects both females and males. Clinical features in affected individuals include intellectual disability, behavioural, and psychiatric abnormalities, epilepsy, movement disorders and gastrointestinal issues. CLCN4, one of the nine members of the CLCN gene family encoding anion-transporting membrane proteins, encodes the ClC-4 protein, a voltage-dependent 2Cl−/H+ exchanger localized in intracellular endo-/ lysosomal membranes and thought to function in ion homeostasis and intracellular trafficking. Although known to have critical functional interactions with CIC-3, encoded by the disease-implicated gene CLCN3, the function of CIC-4 is far from being well understood. Improving our understanding of the biological function of CIC-4, and how different CLCN4 variants affect the functionality of the protein, is an essential step to uncover the pathomechanism(s) and pathophysiology of CLCN4-NDC and to develop disease-specific therapeutic approaches.

Thus, Cure CLCN4 is seeking grant applications towards new or existing projects aimed at improving our knowledge of the fundamental biology of CLCN4-NDC.

Level and duration of funding

We will award a total of £150,000 (2-3 grants of £50,000-£75,000/each). The award will be for 18-months, with an option to apply for a no-cost extension of 6 months. The proposed funding period is 1st April, 2024 to 1st October, 2025.

Scope

While the request for applications is broad in scope, we are especially interested in projects covering the following areas:
1. Understanding of the basic biology and function of the CIC-4 protein.
2. Functional characterization of new CLCN4 variants and/or variants of unknown significance.
3. Characterization of animal models of CLCN4-NDC; with particular interest in the characterization of the Cure CLCN4-funded rat models available from the INFRAFRONTIER repository (get in touch for details). Non-rodent animal models will also be considered.

The ultimate objective of this grant call is to support projects aimed at helping uncover the pathophysiology of CLCN4-NDC, and with it, to pave the way for the development of novel and targeted therapeutic approaches to effectively manage the condition.

How to apply

You can download the application guidelines here, and the application template here (please use a browser other than Mozilla Firefox to download the documents). Completed applications should be emailed to rebeca.rf@cureclcn4.org by 5pm (GMT) on 15th December 2023. If you have any questions about the application please email the Research Program Manager at rebeca.rf@cureclcn4.org .