COMPOSITIONS AND METHODS FOR MODULATION OF THE UNC13A SPLICE

Claims

Antisense oligonucleotides for modulating UNC13A splicing (e.g., inhibiting the inclusion of a cryptic UNC13A exon into a mature UNC13A mRNA), compositions comprising the antisense oligonucleotides, and methods of use are described. Pharmaceutical compositions comprising one or more antisense oligonucleotides and methods for treating a disease associated with UNC13A or a disease associated with TDP-43 dysfunction in a subject by administering the antisense oligonucleotides to the subject are also described.

1. An antisense oligonucleotide comprising a first antisense sequence targeting a first target region and a second antisense sequence targeting a second target region, wherein the first target region and / or the second target region each comprise a UCN13A sequence, wherein the antisense oligonucleotide modulates the splicing of a UCN13A cryptic exon, wherein the first target region or the second target region comprises a nucleotide sequence as set out in SEQ ID No. 313 or SEQ ID No.

315.

41. A composition comprising the antisense oligonucleotide of any of claims 1-40.

55. A pharmaceutical composition for use in a method for inhibiting the inclusion of a cryptic UNC13A exon in a mature UNC13A mRNA and / or restoring UNC13A expression in a subject cell, comprising a therapeutically effective amount of the antisense oligonucleotide of any of claims 1-40.

56. A pharmaceutical composition for use in the treatment of a disease associated with abnormal expression of UNC13A in a subject comprising a therapeutically effective amount of the antisense oligonucleotide of any of claims 1 to 40.

57. A pharmaceutical composition for treating a disease associated with TDP-43 dysfunction in a subject comprising a therapeutically effective amount of the antisense oligonucleotide of any of claims 1-40.