Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model

Hum Mol Genet. 2018 Jul 15;27(14):2466-2476. doi: 10.1093/hmg/ddy151.


Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204+6T>C) that negatively affects the definition of exon 20 in the elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5' splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, exon-specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition. Lentivirus-mediated expression of ELP1-ExSpeU1 in FD fibroblasts improved ELP1 splicing and protein levels. We next focused on a transgenic mouse model that recapitulates the same tissue-specific mis-splicing seen in FD patients. Intraperitoneal delivery of ELP1-ExSpeU1s-adeno-associated virus particles successfully increased the production of full-length human ELP1 transcript and protein. This splice-switching class of molecules is the first to specifically correct the ELP1 exon 20 splicing defect. Our data provide proof of principle of ExSpeU1s-adeno-associated virus particles as a novel therapeutic strategy for FD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / therapeutic use
  • Dependovirus / genetics
  • Disease Models, Animal
  • Dysautonomia, Familial / genetics
  • Dysautonomia, Familial / physiopathology
  • Dysautonomia, Familial / therapy*
  • Exons / genetics
  • Gene Expression Regulation
  • Genetic Therapy*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Introns / genetics
  • Mice
  • Mice, Transgenic
  • RNA Splicing / genetics
  • RNA, Small Nuclear / genetics*
  • RNA, Small Nuclear / therapeutic use
  • Transcriptional Elongation Factors


  • Carrier Proteins
  • Elp1 protein, human
  • Ikbkap protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Nuclear
  • Transcriptional Elongation Factors
  • U1 small nuclear RNA