Research summary of recent leukodystrophy research and clinical trials, includes article summaries and direct links to websites and articles.
Clinical trial updates
BridgeBio Receives FDA’s Regenerative Medicine Advanced Therapy (RMAT) Designation for BBP-812 Canavan Disease Gene Therapy Program
Research summaries
Adrenoleukodystrophy (ALD)
Alternative therapeutic approach to haematopoetic stem cell transplantation in early cerebral adrenoleukodystrophy (cALD)
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae261/7729175
This scientific commentary discusses the current and potential treatment options for cALD. The current established treatment for cALD is allogeneic haematopoietic stem cell transplantation (HSCT). Bone marrow cells are harvested from a genetically matching healthy donor and injected into the individual with cALD. While this treatment can stabilise cerebral lesions, there are several constraints to HSCT use, such as the lack of suitable donors, access restrictions, transplantation-related risks and delays in treatment outcomes hampering its benefits for advanced cALD. A non-invasive oral treatment, leriglitazone, has been recently proposed as an alternative to HSCT. The phase 2-3 ADVANCE study suggested a positive effect on the development and progression of severe cALD. In boys aged 2-12 years, the NEXUS trial showed encouraging results with lesions stabilisation within 24 weeks of treatment with a once-daily oral leriglitazone. More recently, a clinical trial investigated leriglitazone treatment in a small cohort of adults ineligible for or awaiting HSCT. Evidence of clinical and radiological disease stabilisation has been reported for 10 out of the 13 adult cALD individuals, and the treatment was generally well tolerated. Given the positive outcomes, transplantations were deferred for all the patients awaiting HSCT. Similar to HSCT, leriglitazone has a greater therapeutic impact at early stages of cALD. While additional larger randomised studies are required to confirm the efficacy and safety of leriglitazone in cALD, this treatment presents as an interesting alternative to HSCT when HSCT is not possible, not available or was not successful.
Burden of illness and mortality in men with Adrenomyeloneuropathy: a retrospective cohort study
https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03276-w
Adrenomyeloneuropathy (AMN) is a progressive neurodegenerative disorder that affects adult men, leading to symptoms such as difficulty walking, bladder issues and muscle stiffness. This study evaluated the health burden and mortality rates in men with AMN in the U.S. by analysing two large healthcare databases. The study found that men with AMN had significantly higher healthcare resource use compared to men without the condition. This included more hospital admissions, outpatient visits, home healthcare, and prescription drug use. For instance, men with AMN averaged 8.88 outpatient visits per year compared to just 4.1 for those without AMN. They also had a higher rate of other health conditions, such as lung disease, liver disease, and vascular problems. Mortality rates were also higher for men with AMN. Among those under 65, men with AMN had a mortality rate 5.3 times higher than the general population, and they passed away at a younger average age (47 vs. 56 years). For men aged 65 and older, the mortality rate was 2.2 times higher compared to their peers without AMN. The findings highlight the significant and often under recognised impact of AMN on health and life expectancy. These men require more intensive healthcare services and face higher risks of early loss of life compared to the general population. The study highlights the need for better management and support for men living with AMN.
CSF1R-Related Disorder – Prevalence of CSF1R Variants and Their Clinical Significance in the UK Population
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11261581
CSF1R-related disorder (CSF1R-RD) is a spectrum of white matter disorders genetically involving the CSF1R protein and clinically characterised by various cognitive impairments, neuropsychiatric changes and motor symptoms. Given the non-specific clinical presentations and lack of access to genetic testing, CSF1R-RD is thought to be frequently misdiagnosed. Thus, the number of affected individuals, or prevalence, is most likely underestimated. To better understand the prevalence of CSF1R genetic variants and their pathogenicity, researchers examined the whole genetic code of 470,000 adults from the UK Biobank study. They identified a total of 62 CSF1R variants in 132 carriers. Using the American College of Medical Genetics (ACMG) criteria, researchers classified the 132 mutation-bearer individuals into 25 pathogenic variant carriers and 107 likely pathogenic variant carriers. These data suggest that around 1 in 3,500 individuals carry a pathogenic or likely pathogenic mutation in CSF1R. Researchers further analysed the medical history of the 132 variant carriers compared to 20,000 random controls. They found an increased likelihood of a psychiatric diagnosis and self-reported Parkinson’s disease in individuals with pathogenic CSF1R variants. They also found a higher probability of dementia and vascular dementia occurrence in those with either pathogenic or likely pathogenic variants compared to controls. This study provides large-scale data and concludes that the frequency of damaging CSF1R variants and CSF1R-RD may be higher than previously described.
Assessing Chitinases and Neurofilament Light Chain as Biomarkers for Adult-Onset Leukodystrophies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11120026
This study investigates the role of chitinases (CHIT1 and CHI3L2) and neurofilament light chain (NfL) as prognostic and diagnostic biomarkers for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a condition linked to mutations in the CSF1R gene. This study involved 63 participants across five groups: healthy controls, patients with ALSP, asymptomatic CSF1R mutation carriers, individuals with other leukodystrophies, and those with ALS. Key findings show that ALSP patients exhibited significantly elevated levels of CHIT1, CHI3L2, and NfL compared to healthy controls, asymptomatic carriers, and individuals with other leukodystrophies. These biomarkers were also related to clinical outcomes, including fatigue, depression, cognitive decline, anxiety, and decreased quality of life. Notably, asymptomatic CSF1R carriers showed elevated CHIT1 and NfL levels, suggesting subclinical axonal damage and inflammation, even in the absence of obvious clinical symptoms. The study highlights the potential of chitinases and NfL as biomarkers for early disease detection and prognosis in ALSP. The findings suggest that these biomarkers may help distinguish ALSP from similar conditions and monitor disease progression. However, limitations of this study include the small sample size and retrospective design, which limit the ability to understand long-term biomarker trends. Therefore, this study calls for further research in larger cohorts to confirm the utility of these biomarkers in ALSP and related disorders.
Plasma concentrations of glial fibrillary acidic protein, neurofilament light, and tau in Alexander disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11305938
Alexander disease (AxD) is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene, primarily affecting astrocytes. Researchers in this study explored the potential of blood-based biomarkers to track disease progression and treatment response in AxD patients. They measured plasma levels of neurofilament light (NfL), GFAP, phosphorylated tau (p-tau), and amyloid-beta (Aβ) proteins in 49 AxD patients and 31 healthy controls. Key findings revealed that regardless of age at disease onset, GFAP was significantly elevated in all AxD patients. NfL and p-tau were also elevated but to a lesser extent, especially in patients with infantile onset, which is associated with more severe disease progression. Moreover, levels of Aβ40 and Aβ42 remained unchanged across all groups. The elevation of GFAP in plasma confirms its potential as a useful biomarker, although its levels might be affected by treatment strategies targeting GFAP, such as antisense oligonucleotides (ASOs). Therefore, additional biomarkers like NfL and p-tau, which are less directly impacted by treatments, may provide complementary information on disease status. This study highlights the potential of GFAP, NfL, and p-tau as biomarkers for AxD, emphasising their role in assessing disease progression, especially in cases with early-onset and severe forms of the disorder. However, further research is needed to validate these findings and explore their longitudinal application in clinical settings.
Metachromatic leukodystrophy (MLD)
Improving newborn screening test performance for metachromatic leukodystrophy: Recommendation from a pre-pilot study that identified a late-infantile case for treatment
https://www.sciencedirect.com/science/article/pii/S1096719224002348?via%3Dihub
In this study, the researchers explored a new method to screen newborns for metachromatic leukodystrophy (MLD), a rare but severe genetic disorder that affects the brain and nervous system. MLD is caused by a deficiency in the enzyme arylsulfatase A (ARSA), leading to the buildup of harmful substances in the body. Early diagnosis is critical as gene therapy can greatly improve outcomes if given before symptoms develop. The screening approach involved a two-step process: first measuring a substance called sulphatide in dried blood spots, and then testing for ARSA enzyme activity in those who tested positive. In this United Kingdom pre-pilot study, 11 babies initially tested positive for sulphatide, but all were found to be negative for MLD in the second step. The researchers confirmed that the method accurately identified MLD negative bloodspots from unaffected siblings of MLD patients and flagged one new case of MLD in a baby, allowing for timely intervention of gene therapy. The study also suggested that lowering the threshold for the first sulphatide test could increase sensitivity and improve detection rates as the new case found had levels lower than would be detected in the initial threshold. A promising new marker, C16:1-OH sulphatide, was identified as potentially more specific for MLD than the standard marker. Overall, the findings support the feasibility of this two-step newborn screening method for MLD. If implemented in wider newborn screening programs, it could lead to earlier diagnoses and treatment for affected babies, preventing severe disability and potentially saving lives.
Exploring the Cost-Effectiveness of Newborn Screening for Metachromatic Leukodystrophy (MLD) in the UK
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270184
Early-onset metachromatic leukodystrophy (MLD), before the age of 30 months, is the most severe and the most common form in the UK. Atidarsagene autotemcel (arsa-cel) is the only disease-modifying treatment approved for early-onset MLD, the earlier the treatment is initiated, the better the clinical benefits. Given the rapid progression of MLD, the time window for treatment is narrow, highlighting the importance of identifying MLD as soon as possible. Recent studies demonstrated the feasibility of MLD screening from dried blood spot samples used for routine newborn screening. For MLD screening to be included in the routine newborn screening program in the UK, the cost-effective use of NHS resources has to be validated by health-economic analyses. To do so, researchers used published data and clinical experience to build a model framework describing the different scenarios for MLD with or without screening and their probabilities. The model has to be the most accurate and representative of the context possible as it is ultimately used to calculate each intervention’s (screening vs. no screening for MLD) long-term costs and health outcomes. A critical measure for the economic evaluation of an intervention is the quality-adjusted life year (QALY), which indicates how well an intervention lengthens and improves an affected individual’s life. The total cost (screening, care, medication) and QALY were assessed for each intervention individually and then used to calculate the incremental cost-effectiveness ratio (ICER). Based on their model, researchers found an ICER for screening vs. no screening for MLD of £33,212/QALY gained. An intervention is stated as cost-effective when the ICER stands below the willingness-to-pay threshold set by the National Institute for Health and Care Excellence (NICE). For standard appraisal, the threshold is £20,000-30,000/QALY gained, but this can be increased to £50,000/QALY gained depending on the severity of the disease. MLD fits in this latter category; therefore, this study concludes that implementing screening for MLD is clinically relevant and a cost-effective use of NHS resources. These findings are promising for including MLD in the routine newborn screening program in the UK.
Vanishing White Matter Disease (VWMD)
In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice
Vanishing white matter disease (VWMD) is a juvenile genetic neurodegenerative disease dominated by progressive motor decline. Disease-causing mutations are located on the EIF2B1-EIF2B5 genes that encode the different subunits of the translation inhibition factor 2B (eIF2B), a key factor in protein synthesis. When eIF2B is dysfunctional, the integrated stress response (ISR) gets activated, leading to the downregulation of all other protein synthesis. In this study, researchers investigated the use of in vivo CRISPR-mediated base editing technology to directly correct the underlying genetic defect at the DNA level. A DNA strand is a succession of four bases named adenine (A), guanine (G), thymine (T) and cytosine (C). The order of these bases is crucial for producing a functional protein, meaning that a mutation (substituting one base for another) can have dramatic consequences. For instance, in both Eif2b4P244L and Eif2b5R191H pathogenic variants, the substitution of a G to an A at a specific location on the DNA is the cause of dysfunctional eIF2B protein and VWM pathology. To correct these defects, researchers used an adenine base-editing approach to convert A to G and tested this treatment in mouse models. They used adeno-associated viral vectors (AAV) to deliver the treatment to the brain ventricles of newborn mice and observed a stable correction rate of around 30% in the brain of both Eif2b4P244L and Eif2b5R191H animals up to 8 months post-injection. They further analysed the clinical consequences of such correction in the female Eif2b5R191H mouse model and showed improved bodyweight and restored grip strength. In contrast, motor skills and balance continued to deteriorate. At the tissue level, the correction rate was associated with decreased ISR response in certain brain regions. Brain astrocytes had a higher base-editing rate than oligodendrocytes and increased cell maturation markers. However, researchers also report some non-negligible off-target edits (4.8% on average) that could contribute to motor function decline in treated animals, including controls. In conclusion, this study reported therapeutic potential for base-editing but also highlighted limitations that must be addressed before moving forward.
Concise Articles
Aicardi-Goutieres Syndrome (AGS)
ImmuneSensor Therapeutics Granted New U.S. Patent for its Oral cGAS Inhibitors
https://www.immunesensor.com/news/091724
GM1 gangliosidosis and GM2 Gangliosidosis
Positive Niemann-Pick disease type C (NPC) and GM2 gangliosidosis data from nizubaglustat Phase 2 RAINBOW study conducted by Azafaros presented at major metabolic disease conferencehttps://www.azafaros.com/news/positive-niemann-pick-disease-type-c-npc-and-gm2-gangliosidosis-data-from-nizubaglustat-phase-2-rainbow-study-conducted-by-azafaros-presented-at-major-metabolic-disease-conference/l188c14