Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited autosomal dominant disorder characterized clinically by progressive muscle degeneration. Currently, no curative treatment for this disorder exists. FSHD patients are managed through physiotherapy to improve function and quality of life. Over the last two decades, FSHD has been better understood as a disease genetically characterized by a pathogenic contraction of a subset of macrosatellite repeats on chromosome 4. Specifically, several studies support an FSHD pathogenesis model involving the aberrant expression of the double homeobox protein 4 (DUX4) gene. Hence, potential therapies revolving around inhibition of DUX4 have been explored. One of the potential treatment options is the use of effective antisense oligonucleotides (AOs) to knockdown expression of the myopathic DUX4 gene and its downstream molecules including paired-like homeodomain transcription factor 1 (PITX1). Success in the suppression of PITX1 expression has already been demonstrated systemically in vivo in recent studies. In this article, we will review the pathogenesis of FSHD and the latest research involving the use of antisense knockdown therapy.

Keywords: Antisense oligonucleotide therapy; DUX4; PITX1; gene therapy; morpholino; skeletal muscle.

Figure 1.

Role of chromosome 4q35 D4Z4 repeat array in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). While contraction of D4Z4 repeats in FSHD1 results in the expression of DUX4 and subsequent myopathy, expression of DUX4 in FSHD2 is due to a mutation in the SMCHD1 gene.

Figure 2.

Molecular structure of various antisense oligonucleotide chemistries derived over the years. New generations of antisense chemistries such as 2′O-methylated antisense oligonucleotides (2′OMePS) and octa-guanidine dendrimer conjugated PMOs (vPMO) are artificially modified to improve delivery into target cells.