RNA interference mediated therapy for adult-onset autosomal dominant leukodystrophy (ADLD)

The present invention concerns RNA interference mediated therapy for Adult-onset autosomal dominant leukodystrophy (ADLD), a slowly progressive neurodegenerative disease caused by an excessive lamin B1 (LMNB1) production due to gene duplications or to an alteration in the lamin B1 regulatory landscape.
ADLD is a hereditary, progressive and fatal disorder affecting myelin in the central nervous system. Since, ADLD is caused by LMNB1 gene duplication-mediated overexpression, the paramount choice for ADLD treatment would be a drug capable of restoring physiological levels of LMNB1 expression. We developed the first therapeutic option for ADLD. Our therapeutic strategy is able to restore physiological LMNB1 levels in ADLD patients exploiting allele-specific siRNAs (ASP-siRNAs) targeting a frequent polymorphism in heterozygous state in patients. These ASP-siRNAs are able to silence specifically one Lamin B1 allele (the extra copy) in the genome of ADLD patients, maintaining transcriptionally active the two physiological LMNB1 alleles, as in control subjects. The treatment represents the first therpaeutic option for ADLD and a proof-of-concept in the use of ASP-silencing as treatment for genetic disorders due to gene duplications.

• The inhibition of one specific allele is predicted to avoid excessive and potentially dangerous knockdown of the target gene
• High specificity
• Unlikely off-target effects

Filing date: 25/10/2017

Application number: 102017000121288