2 June 2023
A selection of recent research publications have been summarised below with links to each article.
A study led by BDSRA Australia Medical Advisory Board member, Prof. John Grigg (pictured) has revealed several ocular biomarkers (biological markers) specific to CLN3 disease that may assist clinicians in making timely, early diagnosis, and assist in monitoring ongoing disease progression. The study, Early recognition of CLN3 disease facilitated by visual electrophysiology and multimodal imaging, reviewed ophthalmological assessments of 5 confirmed CLN3 patients from Australia, and found there were several ocular changes common to all patients. Those changes included 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 colour 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 Australia, Prof. Grigg said “Early diagnosis is paramount for enabling patients timely access to supportive interventions as early as possible, for families to receive appropriate family counselling, and to maximise 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.” Congratulations to Prof. Grigg, to co-author and fellow BDSRA Australia Advisory Board member Dr Alex Johnson, and to all contributing authors.
Seizures are one of the primary symptoms of CLN2 disease, but exactly why these occur has remained a mystery. This study shows for the first time that mice carrying a common CLN2 disease-causing mutation also have spontaneous seizures, often so severe they are fatal. Treatment with gene therapy prevented seizures, improved walking ability and prolonged lifespan in CLN2 mice. The research team, led by Professor Jon Cooper at Washington University in St. Louis, Missouri USA, show that seizure activity in CLN2 mice is caused by the loss of a specific population of ’inhibitory’ nerve cells in certain areas of the brain that normally damp down brain activity. Prof. 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. 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 in The Journal of Clinical Investigation and supports an ongoing clinical gene therapy program sponsored by Regenxbio, which includes 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: Early data support Regenxbio's gene therapy program for CLN2 disease: Gene therapy eases signs, symptoms in mouse model of late infantile Batten
A new study, co-authored by BDSRA Australia Medical Advisory Board member Prof. Ingrid Scheffer, has characterised 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 analysed 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 decade. A more in-depth summary of the study and conclusions can be found here: Seizures in protracted CLN3 disease start later, delaying diagnosis: Genetic analysis uncovers features of this rare, milder form of juvenile Batten
This recent study has shown that changes in the levels of certain metabolites in 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 from the National Institutes of Health in Bethesda, Maryland (USA) 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: Changes in brain metabolites may be biomarkers for CLN3 disease - Markers of disease severity may be useful in clinical trials: Study
This cell-based study suggests that 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
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. Read more here.