Antisense Oligonucleotide-Mediated Therapeutic Intervention for Malan Syndrome

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Awardees: Dr. Jessica Cale (Principal Investigator), Isabella Trew, Dr. May Aung-Htut and Dr. Steve Wilton

 

Institution: Murdoch University

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Grant Amount: Year 1- $30,000 USD; Year 2- $30,000 USD

 

Funding Period for Year 2: February 1, 2024 - February 1, 2025

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Summary:

 

Malan syndrome is a rare condition that causes excessive growth within the brain, bone abnormalities, unique facial features, learning disabilities, and vision issues. The main cause of Malan syndrome is specific changes in a gene called NFIX, resulting in insufficient levels of the NFIX protein (NFIX haploinsufficiency). Our research team, supported by the Malan Syndrome Foundation, has been investigating ways to increase the expression of NFIX using molecules called antisense oligonucleotides (ASOs).

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In Year 1 of this study, funded by the Malan Syndrome Foundation in 2022, we carefully designed and tested 44 different ASOs in an effort to boost NFIX gene and protein levels. We discovered that two of these compounds effectively and statistically increased NFIX gene expression in neuronal-like cells and patient-derived fibroblasts, which are cells taken from individuals with Malan syndrome.

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Since there is limited information available on NFIX expression patterns, our Year 2 research aims to experimentally determine the different forms of NFIX produced in various patient-derived cells, particularly in the region that controls its initial production – the start of the gene. This comprehensive understanding of NFIX gene transcript composition at the beginning will enable us to refine our therapeutic compounds for testing in patient cells that have been transformed into nerve cells, a crucial step in understanding the disease as the nervous system appears to be a major affected region in Malan syndrome. By uncovering the complexities of NFIX gene regulation and optimizing our therapeutic compound approach in patient nerve cells, we hope to bring us closer to a potential disease modifying treatment for Malan syndrome.

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