Posters

Water Determination in Sulfurization Reage

Sulfurization reagents are often used instead of oxidation reagents in solid phase oligonucleotide synthesis utilizing phosphoramidite chemistry, in order to produce phosphorothioate oligonucleotide analogues. However, water contamination in the sulfurization reagent can cause oxidation to occur instead of thiolation. It is therefore important to have low water content in sulfurization reagents to minimize oxidation. In this poster we will outline methods for the determination of water content in the solid and dissolved sulfurization reagents, DDTT and xanthane hydride. In addition, we will show the water content results that we obtained from our Karl Fischer titration experim

Sandra Lorenz, Senior Scientist, Honeywell
MS degree in physical chemistry from Iowa State University -Currently a scientist at Honeywell working with high purity solvents and oligonucleotide reagents (19 years).

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VP-001 as an interventional therapy for patients with PRPF31 mutation-associated retinal dystrophy

Antisense oligomers (AOs) are synthetic nucleic acid analogues that can be designed to modify pre-mRNA splicing or protein expression for the treatment of genetic diseases. Despite advances made through chemical modifications to improve intracellular penetration and durability, suboptimal AO delivery presents an ongoing challenge and limits the realisation of potential therapeutics. Antisense therapies for retinal diseases are particularly limited by inadequate productive uptake in the retina. Herein we show that VP-001, a cell-penetrating peptide-PMO (PPMO) conjugate targeting CNOT3 is a potential interventional strategy for patients with the inherited retinal disease PRPF31 mutation-associated retinal dystrophy, also known as retinitis pigmentosa type 11 (RP11). Currently, there are no approved treatments, nor any products in clinical development to our knowledge, specific to patients with RP11. As a genetic condition (prevalent in approximately 2,500 to 4,000 people in the United States), RP11 has a significant health impact on patients, including nyctalopia and progressive losses in visual field which can advance to blindness within their first two to three decades of life. VP-001 is a PPMO that is complementary to CNOT3, which is a negative transcriptional regulator of PRPF31. VP-001 mediates skipping of exon 17 of CNOT3, which knocks down CNOT3 protein leading to increased PRPF31transcription. The peptide enhances uptake of the PPMO into cells compared to unconjugated “naked” PMO. A dose-dependent decrease in CNOT3 protein expression and subsequent increase in PRPF31 expression has been observed across both ARPE-19 and patient iPSC-RPE cells. Scanning electron micrographs show that upon treatment of patient iPSC-RPE which exhibit irregular morphology, the polygonal morphology characteristic of healthy or isogenic controls is recovered. The safety and pharmacokinetics of VP-001 have been assessed upon intravitreal administration in rabbits and monkeys, with results supporting a three-monthly dosing interval and establishing minimal systemic exposure. An ongoing, observational, prospective, longitudinal natural history study is currently underway, and a single ascending dose (SAD) study in RP11 patients will be commenced in H1 2023. The SAD study will assess the safety of VP-001, with participants being followed for 48 weeks.

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Anna Mills, Senior Scientist, PYC Therapeutics