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Leber Congenital Amaurosis

What is Leber Congenital Amaurosis?

Leber congenital amaurosis (LCA) is a rare genetic retinal disorder that usually presents as an early onset potentially blinding visual dysfunction. The main clinical features are severe visual impairment, nystagmus, fundus pigmentation, and severely abnormal electroretinogram within one year of birth. LCA is caused by mutations in critical genes that affect retinal function. There are as many as 17 LCA classifications based on the mutated chromosome number and the position of the specific affected gene, with the most common being LCA types 2 and 10.

Application of Gene Therapy in Leber Congenital Amaurosis

While LCA usually results in progressive vision loss, new advances in gene therapy offer hope for some patients. This new therapy is a promising treatment for LCA, which involves implanting new genes into abnormal retinal cells to correct the defective gene. The vector is designed to target retinal cells affected by the genetic mutation, allowing the functional gene to be expressed and restoring their function.

Fig. 1 Overview of LCA retinal gene therapy.Fig. 1 Overview of LCA retinal gene therapy. (Chiu W, et al., 2021)

One of the most promising candidates for gene therapy in LCA is the RPE65 gene. Mutations in the RPE65 gene are responsible for a significant proportion of LCA cases. Gene therapy targeting this gene has shown promising results in clinical trials. Spark Therapeutics' vision restoration RPE65 gene therapy (LUXTURNATM) has received marketing approval from the U.S. FDA, making it the first gene therapy to receive regulatory approval in the U.S. for the eye or any inherited condition. LUXTURNA™ is a gene therapy product for LCA type 2 that restores retinal function in patients by delivering functional RPE65 protein to the retinal pigment epithelium, requiring regular injections. The therapy has been shown in clinical trials to restore vision in patients with LCA caused by the RPE65 gene mutation. And it is expected to be effective in patients with retinitis pigmentosa (RP) caused by RPE65 mutations.

Current Gene Therapy Clinical Trials in Leber Congenital Amaurosis

Several clinical trials are currently underway to investigate the safety and efficacy of gene therapy for LCA, targeting different genes associated with the disorder. One of the treatments is LCA1 (GUCY2D) gene therapy. Atsena is conducting a Phase 1/2 clinical trial for gene therapy for LCA patients caused by GUCY2D gene mutations. In the trial, nine patients who received the highest dose of therapy showed improvements in their retinal sensitivity and ability to navigate a low-luminance mobility course.

Odylia is developing an adeno-associated virus (AAV)-based gene therapy for LCA caused by RPGRIP1 mutations. An earlier study showed that gene therapy could save degenerated rod cells and cone cells in the mouse model of the disease. Future plans include generating clinical-level gene therapy vectors for toxicology research and clinical trials.

In one study, gene therapy targeting the CEP290 gene was shown to improve vision in animal models of LCA caused by mutations in the CEP290 gene. The therapy involved delivering a functional copy of the CEP290 gene to the retinal cells of the animals using a viral vector. The study demonstrated the safety and efficacy of gene therapy for LCA, leading to the initiation of clinical trials to investigate the therapy in humans.

Opus's lead program, OPGx-001, aims to address mutations in the LCA5 gene encoding the lebercilin protein. The company has received authorization to conduct a Phase 1/2 clinical trial for LCA5 gene therapy at the University of Pennsylvania. This is an important step forward in the development of new treatments for LCA5, which is one of the most severe forms of LCA.

In conclusion, gene therapy has overcome many obstacles and has enabled the translation from basic scientific advances to clinical development. It has proven to be relatively safe in several clinical trials, offering hope to LCA patients.


  • Chiu, W.; et al. An update on gene therapy for inherited retinal dystrophy: experience in Leber congenital amaurosis clinical trials. International journal of molecular sciences, 2021, 22(9): 4534.

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