Galloway Mowat syndrome is a very rare autosomal recessive genetic disorder, consisting of a variety of features including hiatal hernia, microcephaly and nephrotic syndrome. Cause
The exact genetic defect in Galloway Mowat syndrome is yet to be discovered. However, mutations in podocyte proteins, such as nephrin, alpha-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. There is reduced expression of synaptopodin, GLEPP1, and nephrin in Galloway-Mowat syndrome, but these are likely secondary to the proteinuria, likely not the proteins mutated in Galloway-Mowat syndrome.The biochemical lesion appears to be in the Kinase, Endopeptidase and Other Proteins of small Size (KEOPS)/Endopeptidase-like and Kinase associated to transcribed Chromatin (EKC) (KEOPS/EKC) complex. Sequencing of genes in 37 cases of this condition revealed mutations in the OSGEP, TP53RK, TPRKB and LAGE3 genes all of which encode subunits in the KEOPS complex. Members of this complex are found in bacteria, archaea and eukaryotes and are highly conserved. The function of this complex is still under investigation.The biochemical lesion in this condition appears to be in the N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNA pathway. This pathway uses two sequentially acting enzymes - YRDC and OSGEP. Mutations in these genes leads to this syndrome. Genetics
Galloway Mowat syndrome is usually an autosomal recessive disorder, which means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder.
By increasing the quantity of an abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD. Nature and sequence of oligo and target
Eteplirsen is a morpholino phosphorodiamidate antisense oligomer. CTCCAACATCAAGGAAGATGGCATTTCTAG (sequence source: US FDA ETEPLIRSEN BRIEFING DOCUMENT NDA 206488),
30-mer,
20% G,
43% CG,
Predicted Tm: 88.9 °C at 10 μM oligo. Oligo complement
CTAGAAATGCCATCTTCCTTGATGTTGGAG
DMD-001 Exon 51, ENST00000357033.8 in Ensembl.org, RNA target site marked. Given that the target site is within an exon, this is likely blocking binding of an exonic splice enhancer protein and so altering splicing by interfering with splice regulation. CTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCT
CCAAA[CTAGAAATGCCATCTTCCTTGATGTTGGAG]GTACCTGCTCTGGCAGATTTCAACC
GGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGA
GGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAG

Pharmacokinetics
Following single or multiple intravenous infusions, the majority of drug elimination occurred within 24 hours of intravenous administration. Elimination half-life of eteplirsen was 3 to 4 hours. History
New Drug Applications (NDA) for eteplirsen and a similar drug drisapersen were filed with the US Food and Drug Administration (FDA) in August 2015. The Prescription Drug User Fee Act (PDUFA) goal dates for these were December 27, 2015 for drisapersen and February 26, 2016, for eteplirsen. Following FDA rejection of drisapersen, the agency announced a three-month time extension for its review of eteplirsen. The FDA panel decision was controversial because the FDA staff and the panel used a stricter standard of evidence than Sarepta and patient groups used. The FDA panel said that it was required by law to apply the standard of "substantial evidence" of effectiveness. This required randomized, controlled trials showing effectiveness of a meaningful clinical outcome, such as the ability to function in daily life.