The adult onset autosomal dominant leukodystrophy or ADLD, is a genetic, fatal and incurable neurodegenerative disease. It is characterized by a loss of the so-called “white matter” of the central nervous system and is manifested by movement disorders and severe alterations of the autonomic nervous system.

The genetic cause is the presence of three copies, instead of the two normally present, of the gene that contains the instructions to produce the lamin B1 (LMNB1) protein, which belongs to a group of structural proteins (lamins) forming the nuclear membrane of the cell. In patients, Lamin B1 accumulates into the cells causing the neurodegeneration.

Through our project, we will provide the first therapeutic option for ADLD, developing a technique called “allele-specific silencing”. By using small molecules of RNA called “siRNAs”, we will be able to “turn off” one of the three copies of the gene, restoring the physiological lamin B1 levels, and in turn avoiding the accumulation of the protein and the disease.

To validate our therapeutic strategy mediated by siRNAs, we will generate two innovative in vitro models based on induced pluripotent stem cells (iPSC) derived from ADLD patients that will allow an authentic “disease-in-a-dish” approach. The iPSCs are a highly versatile tool, since they can be used to recreate in the laboratory different types of cells normally difficult or impossible to obtain from a patient, such as those of the central nervous system. In these models we will test genetic products already developed in our lab to measure efficacy and potency on LMNB1 reduction and the absence of negative or dangerous effects. Our project is intended to pave the way towards a therapy for ADLD and also establish distinctive human ADLD-relevant models and therapeutic approaches that may have great importance for future studies non only on ADLD but also on the physiopathology and therapy of other leukodystrophies and genetic diseases.

Project financed by ELA up to: 100 000 €