Gene Therapy: a promising potential treatment modality for LCA

Leber congenital amaurosis (LCA) is a congenital retinal disorder that primarily affects the retina. It occurs in 2 to 3 among 100,000 new born and accounts for 10-18% of all inherited blindness or severe visual impairment in children that can alleviate or worsen over a period of time. It is characterized by nystagmus, hyperopia, keratoconus, photophobia, cataract, and glaucoma, and Franceschetti’s oculo-digital sign, behaviour associated with pressing, rubbing or poking of eyes with fingers or knuckles resulting in deep-set eyes and keratoconus. 1 2 Certain genetic subtypes of LCA are also known to cause early onset of renal failure.


With more than 13 identified types of LCA, each type can be differentiated by their impairment pattern, eye abnormalities, and genetic cause. Mutation in more than 25 genes3 that are required for normal development and function of retina can result in the disease and early visual impairment. The genes may be associated with either the development of photoreceptor cells, involved in phototransduction or normal functioning of cilia. While mutations in genes RPE65, CRB1, GUCY2D, and CEP290 are known to contribute majorly, mutations in other genes are also known to cause LCA. Below is the table showing genes and its proportion of contribution in LCA.4


Gene Occurrence
RPE65 3%-16%
GUCY2D 6%-21%
AIPL1 4%-8%
LCA5 ~1%-2%
CRX ~3%
CEP290 ≤20%
RDH12 ~4%
KCNJ13, and
Not certain
IMPDH1 Rare cause of dominant LCA


Situated on chromosome 1’s short arm (p), RPE65 gene encodes a vital enzyme in the retinal pigment epithelium (RPE) needed for regeneration of 11-cis-retinol during the visual cycle. Absence of the enzyme in biallelic mutation of the gene results in the accumulation of toxic precursors that damage the epithelial cells, and loss of photoreceptor cells and vision.


LCA follows autosomal recessive pattern of inheritance and can be diagnosed by Electroretinography (ERG), a technique measuring electrical activity of retina. Children with LCA show lower or absence of the activity. With no surgical or medical therapy available currently, LCA is regarded as an incurable disorder and is mainly managed through symptomatic and supportive. Additionally, refractive error correction, utilization of low-vision aids is also known to benefit affected individuals. However, with several clinical trials underway at institutions like Moorfields Eye Hospital at the University College of London, Universities of Pennsylvania and Florida, and Children’s Hospital of Philadelphia showing positive results of gene therapy for LCA2 caused RPE65 mutation is showing up as a potential treatment option.5


Detection of RPE65 mutations is done using molecular genetic testing using sequencing technologies with clinical symptoms and signs providing vital information about the genes to test for and their order.6 Identifying the genetic cause of an inherited disease, genetic diagnostics helps by confirming the clinical diagnosis, availing appropriate therapeutic methods, and enables clinicians to determine the prognosis and progression of the disorder.7


Gene therapies treat disease by inactivating or replacing defective gene or by introducing a novel gene. Viruses, especially Adeno-associated viruses (AAV) are commonly used for introduction of genes due to their simple structure and biology. Belonging to parvovirus family, AAV need co-infection on other viruses such as adenovirus for replication. Although less immunogenic on comparison chances of triggering an immune response are present. Thus, delivering appropriate dosage without eliciting an immune response that could be dangerous to patient or render the therapy ineffective is a challenge. Among the 12 identified serotypes, AAV1 to AAV 12, AAV2, AAV4, and AAV5 are exclusive for retinal disorders, AAV2 being more common.


Small size of eye allows for small amounts of vector usage and immunological advantage offered by the blood-ocular barrier in eye make it ideal for gene therapy. Various studies are being conducted to check the effectiveness of the therapy in retinal diseases caused by RPE65 variants using AAV vectors for introducing normal copy of the gene subretinaly. Situated on chromosome 1’s short arm (p), RPE65 gene encodes a vital enzyme in the retinal pigment epithelium (RPE) needed for regeneration of 11-cis-retinol during the visual cycle. Absence of the enzyme in biallelic mutation of the gene results in the accumulation of toxic precursors that damage the epithelial cells, and loss of photoreceptor cells and vision.
Gene therapy gained further impetus as a potential treatment in 2017 with U.S. Food and Drug Administration (FDA) approving Luxturna (voretigene neparvovec-rzyl) by Spark Therapeutics, Inc for treating eye disorders caused by RPE65 mutations. Using recombinant AAV vector, Luxturna helps in restoring the normal vision in children and adults by delivering a normal copy of the gene directly to retinal cells that allows for the expression of a protein responsible for converting light to an electrical signal in the retina.8 A phase 3 study conducted on 31 subjects showed that patients who received Luxturna demonstrated significant improvement in effectively finishing the obstacle path even at low illumination in contrast to control group.


In order to analyse the efficacy and safety of unilateral and subretinal injections of AV2 and 4 Le Meur, et al, Molecular Therapy, carried out a study on 9 subjects having RPE65 gene mutation associated LCA. Visual activity and general and ocular tolerance in nine subjects were assessed for a year after administering of the vectors in either low or heavy dosages. In an ancillary study which included six of the above subjects assessment was followed up for 2 to 3.5 years. At the end all of them showed good tolerance for the vector; and visual field improvement and stabilization, enhanced visual acuity in subjects with nystagmus, and cortical activation along with visual field and pathways was observed during Functional magnetic resonance imaging (fMRI) evaluation.9


India also is slowly catching up on gene therapy with currently 10 centres across India concentrating on genetic therapies for various disorders ranging from head and neck cancer, haemophilia, leukaemia, cervical cancer to eye disorders.10Narayana Nethralaya, an eye hospital in Bengaluru, has set up a Centre for Regenerative Medicine, Genetics and Gene Therapy that will be focused on providing genetic care to patients, especially those having LCA.11 12 Government of India is also encouraging the gene therapy research in India by providing financial assistance through organizations like Department of Science and Technology (DST), Department of Biotechnology (DBT), and Indian Council of Medical Research (ICMR), etc. 9


Gene therapy is potential treatment modality that holds promise of curing a disease at the root cause than just alleviating the symptoms. It could be an effective treatment option of future if more researches and clinical studies are conducted to analyse the safety and efficacy of the therapy and regulatory authorities to develop policies in streamlining the process. 10


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