Progressive Loss of Vision in CLN7 Detailed in Mouse Model Study
Imaging of mouse model can be used to test therapeutics, researchers say
Researchers described the natural history of retinal degeneration in a mouse model of CLN7, a form of late-infantile Batten disease, that mimics human patient retinal disease progression.
The study revealed a progressive loss or dysfunction of various types of nerve cells within the retina that relay signals from the eyes to the brain.
According to researchers, clinical imaging of this mouse model can be used to test the effectiveness of therapeutics in treating retinal degeneration in people with the condition.
The study, “Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics,” was published in the journal eBioMedicine.
CLN7 is marked by progressive neurodegeneration caused by mutations in the MFSD8 gene. Such mutations impair lysosomes, the compartment in cells that degrade cellular waste, leading to waste buildup, particularly in nerve cells.
Symptoms include seizures, speech impairment, motor and mental regression, and a loss of vision, with onset around 2 to 5 years of age. However, the mechanisms underlying vision loss in CLN7 patients are not well known.
“The natural progression of vision loss needs to be understood in order to find and test therapeutic approaches for treatment in these patients,” wrote researchers based at the University of Texas Southwestern Medical Center.
As a first step, visual examinations were performed on five children with CLN7, ranging in age from about 4 to 7 years old. Tests showed early progressive vision loss and degeneration.
Mouse model lacking Mfsd8 gene characterized
Then, to better understand the mechanisms of vision loss, the team characterized the retina of a CLN7 mouse model lacking the Mfsd8 gene.
Beginning at 1 month of age, these mice showed a progressive loss, up to 65%, of the outer nuclear layer (ONL) — the retinal layer directly underneath the light-sensing, or photoreceptor cells, called rods and cones.
At 6 months of age, CLN7 mice not only had lost most of the ONL thickness but also showed a significant loss of the inner nuclear layer (INL) located underneath the ONL.
“This is the first time that the loss of the INL, similar to that seen in human CLN7 Batten disease patients, has been shown in this mouse model,” the team wrote.
Activation of microglia, immune cells of the nervous system, was seen in the early (two months) and late (five months) stages of the disease, “indicative of retinal stress,” the team noted.
At the late stage, there was also a loss of bipolar cells, which relay signals from photoreceptor cells to the optic nerve, as well as photoreceptor synapses — the site of electric impulse transmission between photoreceptors and bipolar cells.
Researchers then collected retinal images over six months and found progressive photoreceptor degeneration compared to controls. Optical coherence tomography, which measures retinal layer thickness, showed reduced thickness of up to 25% at three months and about 33% by five months.
Electroretinography (ERG), a test to measure the retina’s electrical activity in response to light stimulation, found a loss of signal strength at two months, which continued to degenerate at four and six months. Consistent with the loss the thickness, electrical signals in the INL significantly declined by 4 months of age and continued to decrease through 6 months.
An examination of individual photoreceptor cells found rod function was similar between CLN7 mice and controls at two months. However, at four and six months of age, there was a reduction in the rod ERG response. Cone ERG responses were also significantly decreased in the early stages of the disease, before one month, and late stages at five months.
Further tests demonstrated transmission defects in ganglion cells — nerve cells at the back of the retina that receive signals from bipolar cells, whose fibers form the optic nerve that extends into the brain.
“We found that the preclinical model showed early signs of synaptic defects, rod-cone photoreceptor degeneration, and late bipolar cell death, resulting in blindness,” the researchers wrote. “The knowledge of the retinal cells affected during CLN7 Batten disease progression allows for therapeutics to be tested that target these specific cell types.
“Our study has provided a baseline for CLN7 Batten disease vision loss that can be used when testing therapeutics in this preclinical model, to lead to future human clinical trials for treating vision loss associated with CLN7 Batten disease.”
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