Sunhawk Vision Biotech, Inc.

microRNA-328 has been reported as a risk factor for myopia development. SHJ002 is an antisense for microRNA-328, and SHJ002 was formulated as ophthalmic solution for a novel microRNA therapy. We aimed to investigate the safety and tolerability of SHJ002 ophthalmic solution in children.

This was a single-center, open-label, first-in-human trial in healthy children (NCT04928144). All subjects received the study medication. The trial had 2 stages. Stage 1 was an intrasubject dose-escalation study, and stage 2 was the highest tolerable dose study. The SHJ002 ophthalmic solution was instilled in a randomly selected study eye in each participant, whereas the other untreated eye served as a negative control. Three participants were assigned to stage 1, and they received eye drops of 3 concentrations (0.025%, 0.08%, and 0.25%), each of which was used for 3 consecutive days. The highest tolerable dose from stage 1 was used in stage 2 where another 9 participants were recruited for 28-day treatment. Ocular assessments, physical examination, and vital signs were measured to evaluate safety and tolerability.

There were 4 boys and 8 girls with a mean age of 12.3 years and a SD of 1.56. All participants were Asians. All 3 concentrations used in stage 1 were well tolerated, and the dose of 0.25% was used in stage 2. There were no reports of discomfort. There was only 1 mild adverse event (punctate keratitis) in the untreated eye in 1 participant, which was deemed as "unrelated to study drug."

SHJ002 is a novel microRNA therapy that uses eye drop instillation. SHJ002 ophthalmic solution is generally safe and tolerable, which warrants further investigations in Phase II and III trials.

gov identifier: NCT04928144.

We previously reported miR-328-3p as a novel risk factor for myopia through a genetic association study of the PAX6 gene. In the present study, we first explored the effects of miR-328-3p on other myopia-related genes, and then tested whether anti-miR-328-3p may be used for myopia control.

The luciferase report assay and transient transfection were used to confirm miR-328-3p target genes. The chromatin immunoprecipitation (ChIP) assay was used to investigate retinoic acid receptor on the miR-328-3p promoter. Mice and pigmented rabbits were induced to have myopia by the form deprivation method, and then anti-miR-328-3p oligonucleotide was topically instilled to the myopic eyes. The axial length was measured to assess the therapeutic effect of anti-miR-328-3p. A toxicity study using much higher doses was conducted to assess the safety and ocular irritation of anti-miR-328-3p.

The report assay and transfection of miR-328-3p mimic confirmed that miR-328-3p dose-dependently decreased both mRNA and protein expression of fibromodulin (FMOD) and collagen1A1 (COL1A1). We subsequently showed that FMOD promoted TGF-β1 expression, and overexpression of FMOD increased the phosphorylation levels of p38-MAPK and JNK. The ChIP study showed that retinoic acid binds to miR-328-3p promoter and up-regulates miR-328-3p expression. In myopic animal studies, anti-miR-328-3p was as effective as 1% atropine and had a dose-dependent effect on suppressing axial elongation. In the toxicity study, anti-miR-328-3p did not cause any unwanted effects in the eyes or other organs.

Micro (mi)R-328-3p affects myopia development via multiple routes. anti-miR-328-3p possesses a potential as a novel therapy for myopia control.