Treatment Potential for LCA5-Associated Leber Congenital Amaurosis

Invest Ophthalmol Vis Sci. 2020 May 11;61(5):30. doi: 10.1167/iovs.61.5.30.


Purpose: To determine the therapeutic window for gene augmentation for Leber congenital amaurosis (LCA) associated with mutations in LCA5.

Methods: Five patients (ages 6-31) with LCA and biallelic LCA5 mutations underwent an ophthalmic examination including optical coherence tomography (SD-OCT), full-field stimulus testing (FST), and pupillometry. The time course of photoreceptor degeneration in the Lca5gt/gt mouse model and the efficacy of subretinal gene augmentation therapy with AAV8-hLCA5 delivered at postnatal day 5 (P5) (early, n = 11 eyes), P15 (mid, n = 14), and P30 (late, n = 13) were assessed using SD-OCT, histologic study, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease.

Results: Patients with LCA5-LCA showed a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and at least 4 log units of dark-adapted sensitivity loss. The Lca5gt/gt mouse has a similarly severe and rapid photoreceptor degeneration. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became nondetectable by P60. Subretinal AAV8-hLCA5 administered to Lca5gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue.

Conclusions: LCA5-LCA is a particularly severe form of LCA that was recapitulated in the Lca5gt/gt mouse. Gene augmentation resulted in structural and functional rescue in the Lca5gt/gt mouse if delivered before P30. Retained photoreceptors were visible within the central retina in all patients with LCA5-LCA, at a level equivalent to that observed in rescued Lca5gt/gt mice, suggesting a window of opportunity for the treatment of patients with LCA5-LCA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Child
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Electroretinography
  • Eye Proteins / genetics*
  • Female
  • Genetic Therapy* / methods
  • Genetic Vectors
  • Humans
  • Leber Congenital Amaurosis / genetics
  • Leber Congenital Amaurosis / physiopathology
  • Leber Congenital Amaurosis / therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics*
  • Optical Imaging
  • Phenotype
  • Pupil / physiology
  • Retina / physiopathology*
  • Tomography, Optical Coherence
  • Visual Acuity / physiology
  • Visual Field Tests
  • Visual Fields / physiology
  • Young Adult


  • Eye Proteins
  • LCA5 protein, human
  • Microtubule-Associated Proteins