An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.

This is an open-label, dose escalation and double-masked, randomized, controlled study evaluating safety and tolerability of sepofarsen administered via intravitreal (IVT) injection in pediatric subjects (<8 years of age) with LCA10 due to the c.2991+1655A>G mutation. The study consists of two parts: an open-label dose escalation part, followed by a double-masked randomized part.

In the open label part; subjects will be assigned to one of 3 planned dose groups using a staggered dose escalation design. After at least 1 patient is dosed in each group; the Data Monitoring Committee (DMC) will review at least 4 weeks of safety data post dosing; and may recommend initiation of the next dose group. The DMC may recommend initiation of the double-masked randomized part of the study after completion of the last dose group in the dose escalation part of the study.

In the double-masked, randomized, controlled part of the study; subjects will be randomized to one of 2 planned dose groups .

Subjects will receive a unilateral IVT injection of sepofarsen on Day 1. Thereafter a 6-monthly dosing schedule is planned.

After each dosing subjects will be assessed for safety and tolerability at follow up visits.

• sepofarsen (Drug), also known as QR-110: RNA antisense oligonucleotide for intravitreal injection

Primary outcomes

• Incidence and severity of ocular adverse events (AEs) [24 months]: Incidence and severity of ocular adverse events (AEs)
• Incidence and severity of non-ocular adverse events (AEs) [24 months]: Incidence and severity of non-ocular adverse events (AEs)

Secondary outcomes

• Change from baseline to Month 12 in Best-corrected visual acuity (BCVA) [12 months]: Mean change in BCVA relative to baseline after 12 months of treatment
• Change from baseline to Month 12 in retinal sensitivity measured by Full-field stimulus testing (FST) [12 months]: Mean change in retinal sensitivity measured by FST relative to baseline after 12 months of treatment

Sex: All, ages: 0 Years to 7 Years

Inclusion Criteria:

* Male or female child, <8 years of age at Screening with a clinical diagnosis of LCA and a molecular diagnosis of homozygosity or compound heterozygosity for the CEP290 p.Cys998X mutation, based on genotyping analysis at Screening. A historic genotyping report from a certified laboratory are acceptable with Sponsor approval.
* BCVA equal to or better than Logarithm of the Minimum Angle of Resolution (logMAR) + 4.0 (Light Perception), and equal to or worse than logMAR + 0.4 in the treatment eye.
* Detectable outer nuclear layer (ONL) in the area of the macula.

Exclusion Criteria:

* Presence of any significant ocular or non-ocular disease/disorder which may put the subject at risk because of participation in the trial' may influence the results of the trial, or the subject's ability to participate in the trial.
* Receipt within 1 month prior to Screening of any intraocular or periocular surgery (including refractive surgery), or an IVT injection or planned intraocular surgery or procedure during the course of the trial.
* Current treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to cytostatics, interferons, TNF-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system).
* Current treatment or treatment within the past 3 months or planned treatment with drugs known to be toxic to the lens, retina, or the optic nerve.
* Use of any investigational drug or device within 3 months or 5 half-lives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the trial period.
* Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.

• ProQR Medical Monitor, Study director, ProQR Therapeutics