Research summary of recent leukodystrophy research and clinical trials, includes article summaries and direct links to websites and articles.
Adrenoleukodystrophy (ALD)
Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy
https://www.sciencedirect.com/science/article/pii/S2095927324004778
In a recent phase 1 clinical trial in China, researchers explored the use of viral vectors for gene therapy in patients with childhood cerebral adrenoleukodystrophy (CCALD). As CALD remains the most progressive and destructive form of adrenoleukodystrophy (ALD), there is a need for more treatments beside allogeneic hematopoietic stem cell transplantation (HSCT). In this trial, seven boys in advanced stages of CCALD were given gene therapy whereby a lentiviral vector (LV) was used to deliver a healthy copy of the ABCD1 gene directly into their brains, aiming to correct the disease-causing genetic defect. The results of the study showed that the gene therapy was well-tolerated with no severe adverse events. There were some mild side effects present, such as fever, loss of appetite and irritability, which were all solved either spontaneously or after managing symptoms. The immune response of the patients was also monitored to make sure that the therapy was not being rejected. In this case, the majority of patients showed minimal immune response, suggesting the body accepted the treatment without significant issues. After testing for the ABCD1 gene in the patients’ blood at 1 month, 3 months, 6-9 months, and 1 year after injection, the expression of the ABCD1 protein increased at the 3 months stage. Although the disease continued to progress in the patients, the therapy successfully introduced the healthy gene into their brain cells and peripheral blood cells, demonstrating the therapy’s ability to distribute the therapeutic gene throughout the body. This research indicates that intracerebral injection of LV-ABCD1 is a safe and feasible approach for treating CCALD. While further studies with larger groups and longer follow-up are needed, this trial marks a significant step toward developing an effective gene therapy in China.
Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10288773
This research article explores Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS), a rare genetic disorder caused by mutations in the CSF1R gene. BANDDOS is an autosomal-recessive condition, meaning both parents must carry the mutation for their child to be affected. The study highlights 19 cases, including 16 from existing literature and 3 new cases from a Brazilian family. The CSF1R gene mutations in BANDDOS disrupt the tyrosine kinase domain, essential for cell signalling. This disruption can result in severe brain abnormalities, developmental delays, and skeletal deformities. Common symptoms include speech disturbances, cognitive decline, muscle rigidity, seizures, and difficulty swallowing. Patients often present with brain calcifications, white matter changes, and structural abnormalities like agenesis of the corpus callosum (full or partial absence of the structure that connects the two halves of the brain) and Dandy-Walker malformation (abnormal development of the brain, primarily the cerebellum which controls body movement). The study highlights significant overlap between BANDDOS and CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP), categorised as an autosomal-dominant condition. While there are genetic similarities, CSF1R-ALSP typically appears in adulthood whereas BANDDOS manifests earlier and more severely, often from birth or infancy. Neuropathological examinations of BANDDOS patients reveal severe white matter degeneration, lack of microglia, and extensive brain calcifications. These findings indicate a common disease mechanism with CSF1R-ALSP but with more pronounced effects in BANDDOS. The article emphasises the potential for using treatments effective in CSF1R-ALSP, such as experimental TREM2 agonists and bone marrow transplants, for BANDDOS. An improved understanding of these disorders could lead to improved therapies for a range of neurodegenerative diseases linked to CSF1R mutations.
Aicardi-Goutières Syndrome (AGS)
The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies https://www.sciencedirect.com/science/article/pii/S1074761324002711#ack0010
Aicardi-Goutières Syndrome (AGS) is a rare genetic childhood disease that affects inflammatory pathways and results in brain injury. AGS is characterised by aberrant interferon-alpha (IFNa) production, but how it affects the brain remains unclear. In this paper, researchers used patient samples and disease models to unravel the source and target of this neurotoxic molecule. First, they showed that AGS individuals had increased IFNa levels in the cerebrospinal fluid (CFS) compared to healthy controls and identified astrocyte cells as the potential source of IFNa in the brain. They then generated a mouse model that repeats these findings to study downstream effects. When they looked at the gene expression profile of all the cerebral cell types, they found that the cells of the vessel walls – called endothelial cells – were the most responsive to abnormal IFNa levels. In this model, long exposure to high IFNa levels is accompanied by vascular dysfunctions called microangiopathy, repeating observations made in AGS individuals. Interestingly, when they genetically removed the receptors to IFNa from endothelial cells, they not only rescued AGS-like brain vessel abnormalities but also reduced AGS-like brain tissue pathology. These findings suggest that endothelial cells are key contributors to IFNa-driven pathological pathways in AGS and open up novel promising paths to therapies.
Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome
Aicardi Goutières syndrome (AGS) is a severe genetic disorder affecting the brain, spinal cord, and immune system, leading to significant neurological impairments. Children with AGS often struggle with motor and expressive language skills, making it difficult to assess their cognitive abilities using standard IQ tests that necessitate motor functions. In a study conducted by researchers at the Children’s Hospital of Philadelphia (CHOP), 57 children with AGS were assessed using two tools: the Leiter International Performance Scale (Leiter-3), which measures nonverbal cognitive skills, and the Vineland Adaptive Behavior Scale (VABS-3), which analyses personal and social skills based on parental reports. The results indicated that compared with communication, daily living skills, and socialisation, motor skills were more severely impacted. Notably, there was a strong relation between the assessments from the Leiter-3 and VABS-3, and the AGS Severity Scale. This similarity suggests that despite their motor deficits, some children with AGS scored within a normal IQ range, demonstrating cognitive potential that standard tests might overlook. The study highlights the importance of using appropriate assessment tools to evaluate cognitive function in children with AGS. These findings can guide clinicians and families in providing better-targeted support and interventions, ultimately helping children with AGS and similar leukodystrophies reach their full communication and educational potential. The research underscores the necessity of patient-centric approaches in clinical trials and treatment plans for AGS and other similar conditions.
A retrospective observational cohort study of the anaesthetic management and outcomes of paediatric patients with Alexander disease undergoing lumbar puncture or magnetic resonance imaging
https://onlinelibrary.wiley.com/doi/10.1111/pan.14937
This study investigates the safety and outcomes of anaesthesia in children with Alexander disease (AD), a rare neurological disorder. AD presents various challenges under anaesthesia due to symptoms such as developmental delays, seizures, and swallowing difficulties. The study reviewed 64 procedures in 40 patients at a specialised children’s hospital to understand patient characteristics, anaesthesia techniques, and complications that may arise. Results showed that 87.5% of the procedures required general anaesthesia or monitored anaesthesia care (MAC), mostly for younger patients. Common symptoms among patients included dysphagia and seizures. Inhalational induction was used in the majority of cases, with very few serious complications reported – only mild hypotension was noted in a small number of cases, which were all managed effectively with routine care. The findings indicate that with proper anaesthetic management, children with AD can safely undergo necessary procedures like MRIs and lumbar punctures without significant risks. The study also highlights that some older patients might tolerate these procedures without anaesthesia, reducing their exposure to potential anaesthetic risks. Overall, this research provides important insights into the safe anaesthetic care of children with this rare disorder, supporting the use of general anaesthesia or MAC with minimal complications.
Cerebrotendinous Xanthomatosis (CTX)
Case report: Cerebrotendinous xanthomatosis treatment follow-up
https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1409138/full
Cerebrotendinous Xanthomatosis (CTX) is a rare neurometabolic disorder characterized by early-onset cataracts, the deposition of cholesterol in the tendons and progressive neurological deficits. To regulate cholesterol metabolism, the first-in-line treatment for CTX is the supplementation of the bile acid called chenodeoxycholic acid (CDCA). In the present report, clinicians followed up on a 22-year-old patient diagnosed with CTX for 18 months to evaluate the effect of treatment with CDCA on disease progression. The patient’s history showed progressive clinical onset, starting with diarrhoea and signs of cataracts, followed by foot deformations accompanied by muscle weakness and tremors. Seven years after the first signs, genetic testing revealed mutations in the CYP27A1 gene and confirmed the diagnosis of CTX. In 2021, the patient was eligible for CDCA treatment, and within a year, biological indicators and some clinical aspects were resolved. Bilirubin and cholestanol levels decreased by 75% and 30%, respectively, and no further mobility deterioration was observed after the treatment initiation. In this case, neurological deficits were not reverted, but the patient’s overall health and quality of life improved. These encouraging results resonate with previous successful observations and highlight the potential of CDCA in halting the progression of the disease.
Intrathecal Gene Therapy for Giant Axonal Neuropathy
https://www.nejm.org/doi/full/10.1056/NEJMoa2307952
Researchers have proposed to replace the defective gene in giant axonal neuropathy (GAN), and the present study reports data from the first-in-human trial. This Phase 1 clinical trial investigated the safety, side effects and best dose of the gene therapy referred to as scAAV9/JeT-GAN. 14 study participants over 6 years old with genetically confirmed GAN each received a single infusion of scAAB9/JeT-GAN into the fluid-filled space around the spinal cord (intrathecal). The primary safety endpoint was the incidence of serious adverse events assessed by clinical, biological and imaging techniques over a median observation period of 68.7 months. The secondary efficacy endpoint was the slowing progression of motor functions assessed by comparing the clinical MFM-32 testing results before and one year after gene therapy. Out of 48 serious adverse events, 1 (fever with vomiting that resolved within two days) was possibly related to treatment, and of all adverse events, 19% were possibly related to treatment and included increased cell count in the cerebrospinal fluid of treated individuals. Regarding preliminary efficacy results, of the four doses tested in this study, only the second highest (1.8 x 1014 viral genome) met the prespecified efficacy threshold one year after treatment. However, researchers noted all-in-all encouraging trends in favour of scAAV9/JeT-GAN gene therapy for slowing down some aspects of motor function decline. This Phase 1 clinical trial is a first step in providing valuable insights for further experimental design involving this route of administration not only in GAN but in other neurodegenerative diseases as well.
Concise Articles
Adrenoleukodystrophy (ALD)
Viking Therapeutics Reports Second Quarter 2024 Financial Results and Provides Corporate Update
Vigil Neuroscience Highlights Publication on ALSP Genetic Mutation Prevalence in Neurology Genetics
Aicardi-Goutieres Syndrome (AGS)
ImmuneSensor Therapeutics Receives Clearance from Australian Regulators to Initiate a First-in-Human Phase 1 Clinical Trial of cGAS inhibitor Drug Candidate, IMSB301
https://www.immunesensor.com/news/081924
Ionis completes enrollment in pivotal trial evaluating zilganersen in people living with Alexander disease
Azafaros announces positive topline Phase 2 study data with nizubaglustat in GM2 gangliosidosis and Niemann-Pick disease type C
GM1 gangliosidosis, Krabbe disease, Metachromatic leukodystrophy (MLD)
Passage Bio Out-licenses Three Pediatric Gene Therapy Programs to GEMMA Biotherapeutics and Enters New Research Collaboration