FEATURED ARTICLE
CLN2 gene therapy rescues spontaneous seizures in Batten mice: now in human trials
Seizures are one of the primary symptoms of CLN2 disease, but exactly why these occur has remained a mystery. This study, led by Professor Jonathan Cooper (pictured left) from Washington University in St. Louis, shows for the first time that mice carrying a common CLN2 disease-causing mutation also have spontaneous seizures, that are so severe they are often fatal. Treatment with gene therapy prevented these seizures, preserved the ability to walk, and prolonged the lifespan in CLN2 mice.
The study findings, which will be presented at the BDSRA Foundation Annual Family Conference in Denton, Texas July 14-16, reveal that seizure activity in CLN2 mice is caused by the loss of a specific population of ’inhibitory’ nerve cells in specific areas of the brain that normally damp down brain activity. In an interview with BDSRA Foundation, Professor Cooper said, ”Knowing about these seizures gives us a new and clinically relevant way to test if therapies are working.”
”We have treated these mice with gene therapy, which supplies a working copy of the disease-causing gene, enabling the missing enzyme to be made,” Cooper said. “This effectively stops any fatal seizures from happening in treated mice, which now live three times as long and can walk normally just like healthy mice. We hope this is a big step towards testing the same approach in children.”
The study, “Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model,” was published on June 15, 2023, in The Journal of Clinical Investigation and supports an ongoing clinical gene therapy program sponsored by Regenxbio, which includes CNS-targeted treatment RGX-181, currently being tested as part of a single-patient study in Brazil.
A more in-depth summary of the CLN2 mouse study can be found here:
PUBLICATION SUMMARIES
A selection of recent research publications has been summarized below with links to each article.
CLN3 disease: Ophthalmological findings are crucial to early diagnosis
A study in CLN3 patients has revealed several ocular biomarkers that appear specific to CLN3 disease may assist clinicians in making timely, early diagnoses and monitoring ongoing disease progression.
The study, “Early recognition of CLN3 disease facilitated by visual electrophysiology and multimodal imaging,” reviewed ophthalmological assessments of five confirmed CLN3 patients in an Australian eye clinic, and found there were several ocular changes common to all patients. Those changes included the early onset of vision decline (median age was 5.1 years), appearance of ‘Bull’s eye maculopathy’ (a ring-shaped area of damage around the macula – the part of the eye responsible for sharp central vision and color perception; see image), reduced electrical activity in the retina, and two distinct, consistent structural changes to the fovea (the central portion of the macula).
In an interview with BDSRA Foundation, study lead Professor John Grigg from the Save Sight Institute in Sydney said, “Early diagnosis is paramount for enabling patients timely access to supportive interventions as early as possible, for families to receive appropriate family counseling, and to maximize the opportunity for patients to access emerging investigational therapies.”
“Monitoring visual function in CLN3 children and adolescents is particularly challenging as neurological deterioration progresses,” he added, “so finding ocular biomarkers that can be consistently recorded in an outpatient setting with less invasive procedures, is important, particularly in terms of endpoints for clinical trials.”
Changes in brain metabolites may be biomarkers for CLN3 disease
This recent study has shown that changes in the levels of certain metabolites in the brains of people with CLN3 disease are significantly associated with multiple measures of disease severity. Measured by non-invasive magnetic resonance spectroscopy (MRS), these biological markers may be useful as surrogate measures of treatment responses in future clinical studies.
Although age accounted for many of these metabolite changes, the levels of some brain metabolites — the byproducts of brain metabolism — were strongly associated with disease severity regardless of age.
The research team led by An Dang Do and Forbes Porter at the National Institutes of Health in Bethesda, Maryland recommended that brain metabolite levels, as measured by MRS, a brain scan similar to an MRI, may be useful as potential and much-needed objective outcome measures in clinical trials.
The study, “Brain proton MR spectroscopy measurements in CLN3 disease,” was published in May in the journal Molecular Genetics and Metabolism.
A more in-depth summary of the study can be found in Batten Disease News here:
Lack of CLN3 harms the process of survival for cells under stress
This cell-based study suggests that the absence of CLN3 protein – the underlying cause of CLN3 disease – leads to poor regulation of cell metabolism and impaired function of protective ’stress granules’ (SGs), which are important for promoting cell survival under stressful conditions.
The study, “The Batten disease protein CLN3 is important for stress granules dynamics and translational activity,” published in the Journal of Biological Chemistry, showed that CLN3-deficient cells had lower metabolic rates and were impaired in their ability to handle additional stressors. Such defects increase cellular stress, making cells with high energy demands, such as nerve cells, more vulnerable to damage.
“With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases,” researchers wrote, “novel insights into the molecular basis of [CLN3] Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.” Read more here.
This summary has been cited from Batten Disease News, April 20, 2023
Modified stem cell therapy extends survival in CLN1 mice
In this study, treatment with stem cells that had been modified to produce PPT1 — the missing enzyme in CLN1 disease — prevented symptoms from developing and substantially extended survival in a mouse model of the disease.
The treatment prolonged survival and slowed disease progression when given to mice that had already developed symptoms. This is “a remarkable result” the researchers wrote in “An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model,” published in EMBO Molecular Medicine in March.
“The findings support further studies on this therapeutic strategy,” they said.
Understanding protracted CLN3 disease; a milder, rarer form
A recent study has characterized seizures and other clinical features of a cohort of patients with the rarer protracted form of CLN3 disease, in order to improve recognition and early diagnosis of the condition.
Compared with the more common ‘classic’ form of CLN3 disease, there has been little research focused on protracted CLN3 disease. In this study, “Recognition and epileptology of protracted CLN3 disease,” phenotypic (clinical) data including electroencephalogram (EEG) recordings was analyzed in 10 patients with protracted CLN3 disease.
The researchers highlighted a later onset of seizures in this cohort, typically in adolescence or early adulthood, a combined focal and generalized seizure presentation, and a longer life expectancy overall, with survival seen into the fifth and sixth decades.
A more in-depth summary of the study and conclusions can be found here:
CLINICAL RESEARCH UPDATES
CLN3 disease – 6-month results in the Phase I/II trial of Batten-1
Earlier this month, Theranexus together with the Beyond Batten Disease Foundation announced preliminary results from the Phase I/II trial of Batten-1 (miglustat) for the treatment of CLN3 disease. After six months of treatment, the preliminary data signals a reduction in neurofilaments (a biomarker of neuronal death), and stabilization of motor symptoms in treated patients, compared with the decline expected with the natural disease course. Batten-1 continued to show a good tolerability profile. Read more here.
Phase 3 of the clinical trial in pediatric patients (age 4-16 years) is expected to be open for enrolment by the end of the year.
