This suggests that eye-targeted CLN2 therapies should be administered before, or as early as possible within, this critical period.
In addition, the data highlighted that two eye tools — optical coherence tomography (OCT) and the Weill Cornell Batten Ophthalmological Severity Scale (WCBS) — effectively captured the progression of vision problems over time and may be used as objective tools to assess treatment response in future clinical trials.
The study, “Symmetric Age Association of Retinal Degeneration in Patients with CLN2-Associated Batten Disease,” was published in the journal Ophthalmology Retina.
CLN2 disease belongs to a group of disorders called neuronal ceroid lipofuscinoses (NCL), in which waste molecules build up inside cells, mainly affecting the brain and the retina — a thin layer lining the back of the eye that sends vision signals to the brain.
While first symptoms typically emerge from ages 2 to 4 in children with CLN2 disease, vision problems tend to develop later, after the onset of motor and developmental deficits. However, OCT imaging — used to create images of the different layers of the eye — was reported to detect signs of retinal damage in CLN2 patients as young as 2.
To date, Brineura (cerliponase alfa, by BioMarin) is the only approved treatment for CNL2 disease in the United States and Europe. Despite its effectiveness in slowing the progression of motor and speech impairment in these children, its benefits in vision-related symptoms seem limited.
That is why “efficacious therapy and a greater understanding of the retinal degeneration and vision loss that continues in these children are needed,” the researchers wrote.
Researchers at Weill Cornell Medicine in New York, set out to characterize the progression of retinal problems over time in children with CLN2 disease who had not received any prior treatment.
They also sought to determine the critical period for retina-directed intervention and the best tools to assess the natural progression of retina-associated disease.
The team retrospectively analyzed the demographic, clinical, and eye data of 42 CLN2 patients. All had undergone a comprehensive ophthalmic examination under anesthesia as part of their participation in a trial (NCT01035424) designed to study CLN2’s natural disease progression.
Vision tests included examination of the fundus (the interior surface of the eye), fundus photography (used to collect images of fundus condition), and OCT. In addition, OCT and fundus images were assigned a score from 1 to 5 based on retinal disease severity using the previously established WCBS.
Patients (24 girls and 18 boys) had a mean age of 47 months (almost 4 years) at the time of diagnosis (range 18–67 months) and 60 months (about 5 years) at first eye examination (range 30–103 months).
Both eyes of each patient were examined at least once, and 13 children underwent several examinations with a mean follow-up period of 15.3 months.
Results showed that children with CLN2 disease had a progressive, bilateral, and symmetric degeneration of the retina over time, and that this progression was faster during a critical period from 4 to 7 years of age.
“This suggests that [retina-specific] intervention early or ideally before this critical period may mitigate visual decline,” the researchers wrote, adding that early diagnosis of CLN2 disease may “provide ample time for retinal therapy before the onset of significant retinal degeneration.”
The team also noted that the high degree of symmetrical progression between both eyes at different stages of progression may lower the number of participants required in a clinical trial, since a therapy’s effectiveness may be evaluated within the same patient by comparing a treated vs. a non-treated eye.
Moreover, compared with fundus photography, OCT appeared to be better at assessing the symmetrical damage between both eyes, and at detecting subtle changes at earlier stages of the disease. WCBS scores based on both OCT and fundus images also accurately reflected the progression of retinal degeneration.
“The WCBS scores and OCT measurements can provide objective biomarkers for the efficacy of retina-directed CLN2 gene therapy, for which the contralateral eye provides an ideal control,” the researchers wrote.
The team also noted that the data supported preclinical and clinical evidence suggesting that retinal dysfunction occurs independently from brain and spinal cord neurodegeneration in children with CLN2 disease. This highlights the importance of better understanding vision-associated symptoms in CLN2 disease and of working on eye-specific therapies.
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