番茄社区

Leber congenital amaurosis (LCA) encompasses a spectrum of inherited retinal diseases (IRDs) and is one of the most severe types of progressive IRD, generally causing significant functional vision decline within the first year of life.

To date, this monogenic autosomal recessive disease has been linked with mutations in more than 25 genes, and affects approximately one in 30,000 newborns. Several gene therapies are being studied that target three of the most common genes associated with LCA: retinal pigment epithelium-specific 65 (RPE65), centrosomal protein 290 (CEP290), and guanylate cyclase 2D (GUCY2D).

Importantly, as with many progressive diseases, early detection and diagnosis are central to outcomes, particularly for patients whose LCA can be treated.

"Patients with LCA typically present at a young age -- anywhere from 3 months of age to the first decade of life," Mark Pennesi, MD, PhD, of the Casey Eye Institute at Oregon Health & Science University in Portland, told 番茄社区. "They may have [various symptoms such as] nystagmus, photophobia, or difficulty in dark conditions, but it is important to realize that LCA can present as a spectrum and some patients have milder features."

"Many patients with LCA see a large number of doctors -- for instance, an infant's abnormal eye movements may prompt a neurology workup with MRI before it is realized they have an ocular problem," noted Jason Comander, MD, PhD, of the Inherited Retinal Disorders Service at Massachusetts Eye and Ear in Boston.

Given that LCA is a progressive disease, "it's important that children with suspected vision loss have an examination with a pediatric ophthalmologist, and then be referred to a retinal specialist when needed," Comander told 番茄社区. "Diagnosis of LCA can be tricky because the retina can sometimes look normal without specialized testing such as an electroretinogram."

He explained that a diagnosis of retinal degeneration in general triggers initiation of genetic testing, which can provide prompt diagnosis, but also sometimes identifies patients who qualify for a clinical trial or for an approved treatment such as voretigene neparvovec (Luxturna), which often results in better outcomes earlier in life.

"A comprehensive evaluation is also important to help understand a patient's current level of functioning, and over time to evaluate their progression rate so they know what to expect without treatment," Comander added.

Indeed, "some genes have been associated with faster progression," noted Pennesi and co-authors in a 2018 . Infants with severe visual impairment may also have delays or difficulties with social skills and behavior, highlighting the importance of early involvement by a developmental pediatric specialist.

Although most IRDs affect only the retina, it's important to evaluate for the possibility of syndromic disease involving other organ systems, Comander said, explaining that ciliopathies such as Bardet-Biedl syndrome, for example, can result in intellectual disabilities or affect the kidneys.

LCA10 is an autosomal recessive ciliopathy, for which the CEP290 intronic variant is the most common mutation. "Depending on the complexity, these workups for systemic disease are sometimes initiated with the help of genetic counselors or by medical geneticists, depending on the gene, the age, and the setting," he said.

Currently, genetic testing is able to reveal a cause of disease in about two-thirds of patients, Comander noted, adding that improving the diagnostic rate is an active area of research, including at his institution. Genetic testing is much easier thanks to sponsored programs offered at no cost to the patient, he added.

Comander said that while promising treatment approaches are being studied, "it's important to provide children and patients of any age with the skills and resources they need to make the most of their vision and to be as successful academically and intellectually despite their visual disability. For example, access to vision rehabilitation services, sometimes through specialized centers, can introduce and train patients on the latest technology for reading and/or audio. We have many patients with severe vision loss who have been able to achieve amazing things with the right resources, support, and environment."

Patients may also access orientation and mobility training, adaptive training skills, and job placement and income assistance provided through .

The current LCA treatment pipeline includes the following:

• For RPE65-LCA (LCA2): "Many of the current clinical trials for inherited retinal disorders like LCA are based on gene augmentation therapy, where a synthetic, correct copy of the gene is delivered to the retina or the retinal pigment epithelium to lead to the production of the missing protein," Comander said. This strategy, used with voretigene for RPE65-associated disease, led to a number of trials using the same strategy, including ongoing trials for retinitis pigmentosa caused by defects in the RPGR gene, he added.

• CEP290-LCA (LCA10): "One particularly exciting development has been the first in-human testing of gene editing in the retina, where the DNA that is already inside the retinal cells is directly edited, instead of bringing in an exogenous copy," Comander said. "This technology is based on CRISPR, and Dr. Eric Pierce at Mass Eye and Ear, and others, including [researchers] at Editas Medicine, are conducting the trial, which is the first test of CRISPR editing in vivo." Trials of gene modulation for LCA include the ProQR antisense oligonucleotide trials of sepofarsen, an investigational RNA antisense oligonucleotide therapy, for CEP290-LCA. Effects of sepofarsen have been described in a recent . In addition, authors of a 2021 of CEP290-LCA's clinical characteristics, societal impact, and investigational treatment strategies noted that "antisense oligonucleotide therapy QR-110 (sepofarsen) has demonstrated encouraging safety and efficacy data in a first-in-human trial; a phase 3 clinical trial is ongoing."

• GUCY2D-LCA: A clinical trial of gene therapy for LCA due to GUCY2D is also ongoing, said Pennesi, with reported. Another strategy to treat or slow down IRDs involves providing "drugs or genes that are neuroprotective, which are meant to slow down the disease without necessarily fixing the underlying problem," added Comander. "One trial for an antioxidant is forthcoming ... For patients with more moderate or severe vision loss, a type of gene therapy called optogenetics is looking promising, where artificial light sensors are expressed in the remaining parts of the retina, potentially restoring some level of vision; there have been some early successes with this approach." Finally, he said, implantation of microchips is an active area for vision restoration as well.

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