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Gene therapy safely and effectively attenuated the signs and symptoms of CLN7 disease, a form of late childhood Batten disease, in cells and a mouse model, a study has shown.

These results supported the initiation of a phase 1 trial (NCT04737460), conducted at Dallas Children’s Hospital, Texas, involving up to four patients, ages 1 to 18.

The researchers reported “strong proof-of-concept evidence” for using the therapy in clinical trials.

The study, “AAV9/MFSD8 gene therapy is effective in preclinical models of ceroid neuronal disease lipofuscinosis type 7was published in the Clinical Investigation Journal.

In CLN7, a defect MFSD8 leads to the accumulation of waste inside lysosomes, the cellular compartment that stores, recycles and degrades waste. Nerve cells are particularly affected, leading to seizures, motor and mental disorders, speech difficulties and loss of vision. These symptoms usually appear in pediatric patients between the ages of 2 and 5.

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A research team led by Steven Gray, PhD, of the University of Texas Southwestern (UTSW) Medical Center, has developed a first-generation CLN7 gene therapy to replace the MFSD8 gene with a functional copy and deliver it to cells by a harmless adeno-associated virus (AAV9).

The therapy is currently being evaluated in a phase 1 clinical trial conducted by the university. Safety and tolerability are the primary study objectives, with secondary outcomes including changes in motor and mental functions and quality of life.

Taysha Gene Therapies won an exclusive option from UTSW to license worldwide rights to the therapy last year, and is working with the university to continue developing a next-generation version.

In this report, Gray and colleagues describe the development of gene therapy (AAV9/MFSD8), from initial testing in cells isolated from a CLN7 patient to full evaluation in a CLN7 mouse model.

For early proof-of-concept experiments, fibroblast cells, the most common cell type in connective tissue, were obtained from tissue biopsies from a CLN7 patient with MFSD8 changes.

Fibroblasts were treated with increasing doses of the gene therapy, resulting in a dose-dependent improvement in lysosomal function, with a two-fold increase at the highest dose. The team reported no significant changes related to toxicity.

Next, the researchers infused a low and high dose of the gene therapy into the space surrounding the spinal cord – a method called intrathecal delivery – of mice lacking both. Mfsd8 genes (one from each parent), seven to 10 days after birth (p7-10), representing a pre-symptomatic phase.

At 4.5 months, both doses of gene therapy fully restored compromised lysosomal activity in mice lacking both Mfsd8 Genoa. Examination of brain tissue revealed that the high dose slowed or prevented signs of disease progression.

The high dose of gene therapy, when given early (p7-10), more than doubled the lifespan of CLN7 mice compared to untreated mice – 16.8 versus 7.8 months. In contrast, a dose given at six months of age showed no survival benefit, “further confirming that CLN7 must be treated early to be effective,” the researchers wrote.

Additionally, untreated CLN7 mice lost weight rapidly beginning at around six months, while gene therapy-treated mice maintained their normal body weight for longer depending on age and dose.

The researchers observed no treatment-related neurological symptoms or systemic disease, suggesting that gene therapy “is effective and safe in this preclinical disease model.”

No signs of behavioral deficits were observed in the animals, as measured by the rotarod test – widely used to assess motor coordination in rodents – or the open-field and marble-burial tests, at the age of 2 to 4 months. At 6 months, untreated CLN7 mice showed significant impairments, but they were rescued by early treatment with a high dose of gene therapy.

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retina |  Batten Disease News |  illustration of a person's eyes and vision

Further testing at 9 months of age showed that all treated animals performed better in the rotarod test than untreated animals, with early treatment being more beneficial. Total distance traveled in the open field test showed significant differences, but hyperactivity remained comparable to controls.

After 12 months, all untreated CLN7 mice were dead, but most treated animals were able to perform the rotarod test. At the high dose, early treated mice were comparable to unaffected controls. At 18 months of age, the only mice still alive were either controls or CNL7 mice treated early with a high dose of gene therapy.

“Taken together, there were significant behavioral deficits from 6 months in the [CLN7] mice and some deficits seen on the rotarod and open field were completely restored in the high dose p7-10 group, with a trend towards improvement in some other treatment groups,” the researchers wrote. “All these results indicate positive effects of the treatment of [gene therapy] in terms of survival and quality of life.

Safety and tolerance testing in healthy mice followed for one year after gene therapy infusion showed no differences in body weight, signs of disease, microscopic tissue findings, or survival compared to untreated mice. infused. Similar safety experiments in rats also showed a broad distribution of MFSD8 DNA through the rat body, with no change in clinical observations, mortality, rotarod performance, body weight, or food consumption.

“The results obtained in these studies demonstrate that AAV9/MFSD8 is both effective and well tolerated in preclinical models, providing strong proof of concept that AAV9/MFSD8 [gene therapy] should be considered for human translation,” the researchers concluded.