New treatments for myasthenia: a focus on antisense oligonucleotides

Abstract

Autoimmune myasthenia gravis (MG) is a neuromuscular disorder caused by autoantibodies directed against the acetylcholine receptor (AChR). Current symptomatic therapy is based on acetylcholinesterase (AChE) drugs. The available long-term current therapy includes steroids and other immunomodulatory agents. MG is associated with the production of a soluble, rare isoform of AChE, also referred as the “read-through” transcript (AChE-R). Monarsen (EN101) is a synthetic antisense compound directed against the AChE gene. Monarsen was administered in 16 patients with MG and 14 patients achieved a clinically significant response. The drug is now in a Phase II study. Further investigations are required to confirm its long-term effects.

Cholinesterase Inhibitors

“…This was the case in cultured primary brain cells (Meshorer et al, 2002), live mice (Cohen et al, 2002;Birikh et al, 2003;Nijholt et al, 2004), and humanoriginated cell lines (Perry et al, 2004). Antisense suppression of AChER was also shown in EAMG rat muscles and in monkey spinal cord neu rons, leaving AChES almost unaffected (Brenner et al, 2003;Angelini et al, 2013). Moreover, antiChEs induce a feedback response and upregulation of the AChER variant, suggesting that they would actually exacerbate AChER overexpression in myasthenic muscles, perhaps explaining their shortlived effect.…”

“…AChER levels rise both in the serum and muscles of experimental autoimmune myasthenia gravis (EAMG) rats and in the serum of myasthenia gra vis (MG) patients (Angelini et al, 2013). In the primate spinal cord, AChER accumulated under handling stress in a cell size-dependent manner, suggesting that the characteristic response of shift in the alternative splicing of AChE premRNA spans different cell types and is piv otal for controlling motor functions.…”

“…Antisense oligonucleotide suppression of nascent AChER mRNA transcripts emerged as an effective means for challenging the hypothesis that AChER was causally involved with these symptoms, as well as a promising therapeutic alternative. Known by the names AS3, EN101, Monarsen, and BL-7040, the AChE mRNAtargeted agent is a 20residuelong antisense molecule, 2′oxymethyl ated at its 3′terminal position (Angelini et al, 2013). It is targeted at exon 2 of AChE mRNA, which is common to the different AChE mRNA splice variants (Soreq and Seidman, 2001;Meshorer and Soreq, 2006).…”

“…The agent is provided in a single daily oral dose, followed by mea surable improvement in muscle functioning (Angelini et al, 2013). The reported effect lasts over 24 h, with a 100fold lower required molar dose than that of pyr idostigmine (Sussman et al, 2012).…”

Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts

“…Thirteen patients showed improved Quantitative MG scores; however, the study was not placebo-controlled. In the following phase IIa study, oral monarsen given for 7 days at a maximum daily dose of 40 mg decreased Quantitative MG scores by 20.3% compared to baseline [118]. Further development of monarsen for MG was discontinued.…”