The FDA has granted Fast Track designation for QR-421a for Usher syndrome type 2 and non-syndromic RP due to mutations in exon 13 of the USH2A
USH2A-related inherited retinal diseases are a group of orphan IRDs associated with mutations to the USH2A
Matthew Goddeeris, Director of Research, at Eloxx, it was reported that: "Eloxx has screened multiple compounds from its ERSG library of read-through agents for potential use in the treatment of inherited retinal disorders with an initial focus on Usher Syndrome, beginning with USH2A
. Multiple Eloxx compounds in preclinical studies have demonstrated: Dose-dependent activity against Usher mutations.
ProQR Therapeutics has received Fast Track designation from the FDA for QR421a, a first-in-class investigational RNA-based oligonucleotide designed to address the underlying cause of vision loss associated with Usher syndrome type 2 and nonsyndromic retinitis pigmentosa (RP) due to mutations in exon 13 of the USH2A
In general, mutations in RHO (rhodopsin), USH2A
, and RPGR genes lead to 30% of all cases of RP.
Further upstream, the most prevalent c.2299delG mutation in the USH2A
gene, responsible for Usher syndrome type 2, was corrected in patient's fibroblasts using CRISPR/Cas9 and HDR .
Worldwide prevalence of arRP-associated mutations is reported as; USH2A
(12%) ABCA4 (8%), PDE6B (7%), CNGB1 (6%), and PDE6A(5%).USH2A mutations are most frequently associated with the arRP variant (c.2299del; p.
Nonviral vectors developed through studies on vector capacity have increased the number of target genes, and genes such as CEP290 in LCA, ABCA4 in SMD, and MYO7A in Type 1 Usher syndrome are currently within capacity Nevertheless, larger genes such as USH2A
still exceed the available capacity.
We found pathogenic mutations in 16 genes, with the most recurrent being ABCA4 for STGD and USH2A
for RP/USH patients.
In total, 8 genes, including MUC16, UNC79, USH2A
, DNAH17, PTPN13, TENM4, PCLO, and PDE1C, were found to be mutated in at least 2 HCC samples (Table 2); 17 candidate somatic mutations located on these genes were further confirmed via PCR-based Sanger sequencing (Figure 2, Table S6).
Next-generation sequencing (NGS) was then applied to two affected family members with RP (III:9 and IV:1), who did not have CYP4V2 mutations, then to identify disease-causing variants in 47 RP-related genes including the PRPF31, CRB1, PRPF8, CA4, TULP1, PRPF3, ABCA4, RPE65, EYS, CERKL, NRL, FAM161A, FSCN2, TOPORS, SNRNP200, SEMA4A, PRCD, NR2E3, MERTK, USH2A
, PDE6B, PROM1, KLHL7, PDE6A, RGR, CNGB1, IDH3B, SAG, GUCA1B, CNGA1, BEST1, TTC8, C2orf71, ARL6, IMPG2, PDE6G, ZNF513, DHDDS, PRPF6, CLRN1, MAK, CDHR1, FLVCR1, RLBP1, SPATA7, AIPL1, and LRAT genes.