Adult-onset Autosomal Dominant Leukodystrophy (ADLD)
https://www.nature.com/articles/s41598-025-91546-3#
Autosomal Dominant Leukodystrophy (ADLD) is a rare adult-onset neurological disorder caused by duplication of the LMNB1 gene, which leads to excessive production of the lamin B1 protein. Lamin B1 plays a structural role in the cell nucleus, and its overexpression disrupts normal brain cell function, resulting in progressive demyelination—the loss of the protective myelin sheath around nerve fibres. Thus, reducing LMNB1 overexpression is an attractive therapeutic pathway for ADLD as there are currently no treatments that target the root cause of ADLD. Other pathological conditions including various types of cancer have also been associated with alterations in LMNB1 levels, particularly poorer prognosis in renal cell carcinoma and pancreatic cancer. In this study, researchers developed a high-throughput screening platform using a mouse model that mimics LMNB1 overexpression. They screened approximately 97,000 small molecules, aiming to identify compounds that selectively lower lamin B1 levels without harming the cells. After an extensive filtering process, they identified two compounds, known as CID 662896 and CID 5308648 that reduced LMNB1 protein levels in both engineered mouse cells and skin cells derived from ADLD patients. Importantly, CID 662896 was shown not to impair cell viability or proliferation, distinguishing it from other known LMNB1-lowering compounds that are toxic to cells. It also demonstrated the ability to cross the blood–brain barrier in animal studies—a key requirement for any drug intended to treat brain disorders. While further studies are needed to understand how this compound works and to test its effects in animal models of ADLD, this research represents a significant milestone. It is the first large-scale effort to identify small molecules that safely reduce LMNB1 levels, offering a potential new path toward therapeutic development for ADLD and related laminopathies.