A successful phase 1 clinical trial of gene therapy for childhood-onset blindness brings glad tidings for many sufferers of the condition. The gene therapy is designed to target RPE65 gene mutation that leads to Leber congenital amaurosis (LCA) by using a recombinant adeno-associated virus (AVV) vector. Recently conducted at the Children’s Hospital of Philadelphia, this research has opened a new avenue of gene therapy for eye diseases in the US. The findings claim the restoration of retinal and visual function in the patients of LCA, which is a fascinating breakthrough.

The research was funded by The Children’s Hospital of Philadelphia, US National Institute of Health, Spark Therapeutics, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics Research to Prevent Blindness, Center for Advanced Retinal, Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation and The Research Foundation, Flanders. The significant results of these findings were also published by The Lancet on June 30, 2016.

In the follow-up phase 1 trial, 11 out of initial 12 patients between the ages of 11 to 46 years who suffered from inherited retinal dystrophy caused by RPE65 mutation were included. In these phase 1 clinical trials, one dose of AAV2 contained 1.5×1011 in 200 microliter which was subretinally injected in the previously uninjected eyes of the patients. The dosages were administered 1.71-4.58 years after the first subretinal injections while the results of the treatment were found to be positive with minor adverse effects noted in few patients.

Experiments were previously carried out in dogs and rats and the results were encouraging enough to enter the first phase of human clinical trials. Despite substantial support from results in non-human primates, the experts feared humoral response against the treatment modality. The field of gene therapy is evolving at a swift pace however the immune system rejections to the vector or gene insertion at wrong site pose hindrance for it to enter large scale clinical trials.

In this particular case, humoral responses to the adeno-associated virus or RPE65 protein or cell-mediated immune response resulting in inflammation and permanently damaging the retinal cells, was feared.  To the relief of scientists, the injections were observed to improve visual functioning steadily without any harmful side effects. However, mild cases of dellen formation (corneal thinning) in three and cataracts (lens clouding) in two patients were reported. The 3-year long follow up, aimed to continue in order to find any long-term increase in side effects or decreased drug efficacy, showed improved efficacy and no major immunogenicity.

Also known as all-trans retinyl ester isomerase gene, the replaced gene was found to restore the visual functions of patients. The otherwise impaired photosensitivity was measured to record the results while white and blue light stimuli were used to measure rod-photoreceptor sensitivity.. On the other hand, red light stimulus was used for the measurement of cone-photoreceptor sensitivity. The treatment efficacy was also tested by recording the visual activity and the angle of resolution of the patients. Additionally, qualitative papillary light reflex and functional vision tests were used to monitor the retinal and central nervous system pathways.

Are You A Carrier Of A Faulty RPE65 Gene? Can Gene Therapy Help?

Affecting about 3 in 100,000 newborns, a faulty RPE65 gene is one of the most common causes of blindness in children. It is an autosomal recessive disorder which can only be passed on to the child if both parents are the carriers of the faulty gene.  Studies have shown that up to 14 gene aberrations can contribute towards the condition however the clinical trials have been conducted to target one of the most prevalent gene mutations at RPE65 gene.

The RPE56 gene encodes retinal pigment epithelium specific protein 65 that is closely linked to the normal vision of the eye. Produced in the epithelial layer surround the retina, this protein is responsible for a cascade of reactions that translate electrical stimuli into vision formation. Due to faulty RPE65  gene, the retina is affected which in turn leads to visual impairment.

In additional to early onset of visual impairment which progresses with time, increased sensitivity to light, farsightedness and involuntary eye movement may also arise.  Furthermore, afferent papillary defects also are observed in patients of this condition as a result of which normal contraction of pupils on light exposure is disrupted. Prior to this gene therapy study, no cure of this disease is present. However, the diagnosis of the condition can be made by genetic screening for the gene variants and by electroretinogram testing.

The results of this study are encouraging but before the gene therapy gets marketing approval, the study has to clear many prior clinical trial and screening steps. Claimed to be the first gene therapy treatment for the condition in the US, a similar study targeting RPE65 gene for Leber congenital amaurosis was conducted by scientists in the University College London in year 2007, whose results were initially published in 2008. However, before the treatment can be accessed by public, further research has to be conducted.