Ataluren: First Global Approval

Abstract

Nonsense mutations are implicated in 5-70 % of individual cases of most inherited diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren (Translarna™) is an orally available, small molecule compound that targets nonsense mutations, and is the first drug in its class. Ataluren appears to allow cellular machinery to read through premature stop codons in mRNA, enabling the translation process to produce full-length, functional proteins. This article summarizes the milestones in the development of ataluren leading to its conditional first approval for nonsense mutation DMD.

Frecuencia de las mutaciones más comunes del gen CFTR en pacientes peruanos con fibrosis quística mediante la técnica ARMS-PCR

“…Estos moduladores del CFTR incluyen potenciadores como el Ivacaftor VX-770 (nombre comercial: Kalydeco®) para pacientes con la mutación G551D, que incrementa el tráfico del cloruro por el canal del CFTR (mutaciones de clase III) (19) ; correctores como el Lumacaftor VX-809 para pacientes con mutación p.Phe508del en forma homocigota, que mejora el plegamiento y el tráfico de la proteína CFTR anormal (mutaciones clase II) y que actualmente es comercializado como Orkambi® (lumacaftor + ivacaftor) (20) ; y otras moléculas como el Ataluren, el cual está siendo evaluado en ensayos clínicos (nivel III), que corregiría las mutaciones que generan la aparición de un codón stop prematuro como la p.Arg1162* (mutaciones de clase I) (21,22) .…”

New approaches to the treatment of orphan genetic disorders: Mitigating molecular pathologies using chemicals

“…In general, it has been estimated that nonsense mutations account for ~11% of all variations that cause inherited disorders and as many as 20% of the protein-coding region located, single base-pair mutations that cause these diseases (Ryan 2014, HGMD 2015. PTCs can originate from nonsense mutations, frameshift mutations, or from aberrant splicing that generates mRNA isoforms that lead , Suwanmanee et al 2002, Scaffidi and Misteli 2005, van Deutekom et al 2007, Kinali et al 2009, Cirak et al 2011, Hua et al 2010, Nlend Nlend et al 2010, Taylor et al 1999, Giles et al 1999 Single-stranded oligonucleotides (ssODNs) (Jana and Deb 2006, Hainrichson et al 2008, Vecsler et al 2011, Peltz et al 2013.…”

“…Further more, it offers the advantages of having no obvious toxic effects and is orally bioavailable (Welch et al 2007, Peltz et al 2013, Ryan 2014. This drug has shown promising results for DMD, other dystrophinopathies, CF, MPS I, and Carnitine Palmitoyltransferase 1A Defi ciency (CPT1A), with the potential of treating a wider range of genetic disorders (Finkel 2010, Sermet-Gaudelus et al 2010, Rowe et al 2012, Peltz et al 2013, Ryan 2014.…”

“…The safety profiles were similar for ataluren and placebo (Rowe et al 2012, Peltz et al 2013, Kerem et al 2014). PTC124/ataluren (Translarna TM -PTC Therapeutics, Inc.) is a small molecule, orally available compound (Finkel et al 2013, Ryan 2014, which is the first drug developed specifically to treat diseases caused by nonsense mutations. Notably, a conditional first approval for the use in European of this drug was achieved for DMD in 2014 (Ryan 2014, EMA 2015.…”

Correction of the exon 2 duplication in DMD myoblasts by a single CRISPR/Cas9 system

“…However, two drugs have recently obtained conditional approval in Europe (Ataluren, a read-through drug for premature stop mutations) 13 and the United States (Eteplirsen, an antisense molecule to restore the open reading frame in patients with mutations correctable by skipping exon 51). 14 Genome editing technology uses synthetic nucleases to introduce targeted modification at specific loci in the genome by exploiting the endogenous cellular DNA repair mechanisms.…”