CLDN11-related hypomyelinating leukodystrophy (HLD22)
Mahmoud Pouladi, Principal Investigator
Sophia Gjervan, PhD Student
Oguz Ozgoren, PhD Student
Sylvia Stockler, Clinical Co-investigator
Simone Race, Genetic Counsellor & Coordinator
CLDN11-related hypomyelinating leukodystrophy (HLD22) is a newly described condition, causing developmental delay, spasticity and myelination deficit in the brain. CLDN11 encodes claudin-11, a tight junction protein enriched in oligodendrocytes, the myelinating cells of the central nervous system.
The exact mechanisms underlying mutant claudin-11-mediated HLD are poorly understood, hampering efforts to develop effective therapies for this disorder.
Our goal is to better understand the molecular, cellular, and neuropathological changes caused by mutant claudin-11 and to evaluate potential therapeutic strategies for this disorder.
We are using a novel mutant claudin-11 knock-in (mcKI) mouse model, and patient-derived induced pluripotent stem cell (iPSC) lines to produce pre-clinical data to support therapeutic development for HLD22. To this end we are also collecting genotype and phenotype information as well as biological materials (PBMCs, fibroblasts) from newly diagnosed patients.
Specific aims of our research are:
Aim 1: Comprehensive phenotypic characterization of mutant claudin-11 KI mice
Aim 2: Delineation of phenotypic abnormalities in oligodendroglia derived from patient iPSCs
Aim 3: Evaluation of silencing of mutant claudin-11 as a therapeutic strategy in mice and iPSCs
References
Riedhammer KM, Stockler S, Ploski R, Wenzel M, Adis-Dutschmann B, Ahting U, Alhaddad B, Blaschek A, Haack TB, Kopajtich R, Lee J, Murcia Pienkowski V, Pollak A, Szymanska K, Tarailo-Graovac M, van der Lee R, van Karnebeek CD, Meitinger T, Krägeloh-Mann I, Vill K. De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy. Brain. 2021 Mar 3;144(2):411-419. doi: 10.1093/brain/awaa410. Erratum in: Brain. 2021 Jun 22;144(5):e48. PMID: 33313762; PMCID: PMC7940174.
Ozgoren OK, Sequiera GL, Ferrari Bardile C, Gjervan SC, Salman A, Lehman A, Turvey SE, Ross CJD, Stockler S, Pouladi MA. Generation of a human induced pluripotent stem cell line from a patient with hypomyelinating leukodystrophy 22 (HLD22). Stem Cell Res. 2023 Sep;71:103174. doi: 10.1016/j.scr.2023.103174. Epub 2023 Jul 28. PMID: 37531724.
Gjervan SC, Ozgoren OK, Gow A, Stockler-Ipsiroglu S, Pouladi MA. Claudin-11 in health and disease: implications for myelin disorders, hearing, and fertility. Front Cell Neurosci. 2024 Jan 17;17:1344090. doi: 10.3389/fncel.2023.1344090. PMID: 38298375; PMCID: PMC10827939.