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Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.

Kalyan Dulla1, Monica Aguila2, Amelia Lane2

  • 1ProQR Therapeutics, Leiden, the Netherlands.

Molecular Therapy. Nucleic Acids
|August 17, 2018
PubMed
Summary

Antisense oligonucleotide QR-110 effectively corrects the common CEP290 mutation causing Leber congenital amaurosis type 10 (LCA10). This promising therapy shows restored gene function and protein expression in preclinical models, advancing to clinical trials.

Keywords:
QR-110oligonucleotideorganoidretinal dystrophystem celltherapy

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Area of Science:

  • Genetics
  • Ophthalmology
  • Molecular Biology

Background:

  • Leber congenital amaurosis type 10 (LCA10) is a severe inherited retinal dystrophy.
  • Mutations in the CEP290 gene, particularly the deep intronic c.2991+1655A>G variant, are the primary cause of LCA10.
  • This common mutation disrupts normal gene splicing, making it a key target for therapeutic intervention.

Purpose of the Study:

  • To design and screen antisense oligonucleotides (ASOs) for correcting the CEP290 splicing defect in LCA10.
  • To identify the most effective and safe ASO candidate for LCA10 treatment.
  • To evaluate the preclinical efficacy, pharmacokinetics, and safety of the lead ASO candidate, QR-110.

Main Methods:

  • Design and screening of a panel of ASOs targeting the CEP290 c.2991+1655A>G mutation.
  • Assessment of QR-110's ability to restore CEP290 mRNA and protein expression in patient-derived fibroblasts and iPSC-derived retinal organoids.
  • Evaluation of photoreceptor cilia restoration in retinal organoids.
  • Pharmacokinetic studies in mice and rabbits to determine retinal distribution and half-life.
  • Safety and tolerability assessment following intravitreal injection in non-human primates.

Main Results:

  • QR-110 was identified as the lead ASO candidate, effectively restoring wild-type CEP290 mRNA and protein expression in LCA10 fibroblasts.
  • Dose-dependent restoration of mRNA and protein function, including photoreceptor cilia length and percentage, was observed in homozygous iPSC-derived retinal organoids.
  • QR-110 demonstrated widespread retinal distribution and a long intraocular half-life (58 days) in animal models.
  • Intravitreal injection of QR-110 was well-tolerated in monkeys, indicating a favorable safety profile.

Conclusions:

  • QR-110 exhibits promising pharmacodynamic, pharmacokinetic, and safety profiles for the treatment of LCA10.
  • The preclinical data support QR-110 as a potential therapeutic agent for LCA10.
  • Ongoing clinical development is underway to evaluate QR-110 in LCA10 patients.