Autosomal Dominant Leukodystrophy (ADLD) is a rare fatal, adult-onset demyelinating disorder that presents in the 4th or 5th decade of life. ADLD patients experience significant disability during the course of the disease and usually survive for only ~10-15 years after the onset of symptoms.  No treatment exists for this fatal disease, representing an urgent and unmet clinical need. ADLD is caused by a duplication of the lamin B1 gene, resulting in increased LMNB1 protein expression and the appearance of nuclear abnormalities. We have developed methodology to quantify those abnormalities by high content analysis with the ultimate goal to perform a high-throughput screen for modifiers of Lamin B1 expression and associated changes in nuclear structure.

In a high throughput screen of over 100,000 chemical compounds, we have identified two promising candidates for further development into the first ADLD treatments.

Papers

Rolyan H, Tyurina YY, Hernandez M, Amoscato AA, Sparvero LJ, Nmezi BC, Lu Y, Estecio MR, Lin K, Chen J, He RR, Gong P, Rigatti LH, Dupree J, Bayir H, Kagan VE, Casaccia P, Padiath QS. Defects of Lipid Synthesis Are Linked to the Age-Dependent Demyelination Caused by Lamin B1 Overexpression. J Neurosci. 2015;35(34):12002-17. Epub 2015/08/28. doi: 10.1523/JNEUROSCI.1668-15.2015. PubMed PMID: 26311780; PMCID: 4549407. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214339/

Nmezi B, Vollmer LL, Shun TY, Gough A, Rolyan H, Liu F, Jia Y, Padiath QS, Vogt A. Development and Optimization of a High-Content Analysis Platform to Identify Suppressors of Lamin B1 Overexpression as a Therapeutic Strategy for Autosomal Dominant Leukodystrophy. SLAS Discov. 2020;25(8):939-49. doi: 10.1177/2472555220915821. PubMed PMID: 32349647; PMCID: PMC7755098. https://pubmed.ncbi.nlm.nih.gov/32349647/