The therapy’s safety and efficacy is currently being evaluated in a Phase 1/2 trial (NCT02725580) in CLN6-Batten disease patients. Sponsored by Amicus Therapeutics, the trial is enrolling by invitation only at Nationwide Children’s Hospital in Ohio. The study is expected to enroll 13 participants, ages 1 and older, who are ambulatory or able to walk with assistance. More information can be found here.
The findings of the mouse study, “Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease,” were published in Molecular Therapy.
Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, comprise a group of fatal childhood neurodegenerative disorders. The diseases, which affect the nervous system, have a wide range of symptoms, including vision loss, lack of motor coordination, and impaired cognition.
These conditions can be caused by mutations in 14 different genes (CLN1 to CLN14), all of which lead to the accumulation of toxic insoluble waste deposits, called lipofuscins, inside cells. One of these genes is CLN6, which provides instructions to make the CLN6 protein, whose function is still not fully understood.
“There are currently over 70 characterized disease-causing mutations in CLN6, with most of these mutations leading to either a complete loss of CLN6 protein or production of truncated [shorter] CLN6 protein products that are thought to be highly unstable and/or non-functional,” the researchers said.
“Given that there is no effective cure for CLN6-Batten disease, we used [a CLN6] mouse model to test the efficacy of introducing functional human CLN6 via adeno-associated virus (AAV)-mediated gene therapy,” they said.
Like other types of gene therapy, this brain-directed treatment focused on delivering a functional copy of the human CLN6 gene using an adeno-associated viral (AAV) vector, AAV9.
They then administered the construct (scAAV9.CB.CLN6) directly into brain cells of newborn mice (one day old) through an injection on the brain’s ventricles — brain cavities filled with cerebrospinal fluid (CSF), the liquid that circulates in the brain and spinal cord.
The construct remained active until the animals reached the age of 18 months. Its sustained expression prevented mice from showing signs of CLN6 disease in the brain, including the accumulation of autofluorescent storage material, called ASM, which is a pigment that accumulates during the normal aging process. It also prevented neuronal loss.
The results showed the gene therapy ameliorated motor and cognitive deficits associated with CLN6 disease, including balance, gait, leg clasping, memory, and learning.
Importantly, a single injection of the construct prolonged mice lifespan from a median of 14 months to 21.5 months. That’s an increased survival rate of 65%.
Finally, to assess the effects of the gene therapy in a larger animal model more closely resembling human patients, the researchers injected the construct directly into the spinal canal — called an intrathecal injection — of three male monkeys who were each 4 years old.
Results showed the therapy remained active up to six months after administration in the brain and spinal cord of these animals. In addition, no significant alterations were found in any of the lab tests performed, suggesting it was safe and well-tolerated.
“Taken together, these results indicate the outstanding efficacy of a single injection of scAAV9.CB.CLN6 into the CSF of [CLN6] mice and safety of scAAV9.CB.CLN6 in both mice and primates. Based on these promising data, this gene therapy construct has moved into a phase I/II safety trial for CLN6-Batten disease patients,” the researchers concluded.