Research summary of recent leukodystrophy research and clinical trials, includes article summaries and direct links to websites and articles.
Clinical trial updates
Adrenoleukodystrophy (ALD)
Viking Therapeutics Announces Results from Phase 1b Clinical Trial of VK0214 in Patients with X-ALD
Results from the Phase 1b clinical trial of VK0214 in adult male patients with adrenomyeloneuropathy showed that it was safe and well tolerated and found that there were reductions in the very long chain fatty acids and plasma lipid levels after 28 days of one daily dosing of VK0214. There were three cohorts, placebo, and two different doses of VK0214 (20 and 40mg).
Aicardi-Goutieres Syndrome (AGS)
ImmuneSensor Therapeutics Initiates Dosing in Phase 1 Clinical Trial of Lead cGAS Inhibitor Drug Candidate, IMSB301
https://www.immunesensor.com/news/100824
The first dose level cohort of healthy volunteers have been dosed in the Phase 1 randomised, double-blinded, placebo-controlled clinical trial for oral cGAS inhibitor drug candidate, IMSB301 that Is being developed for treating several inflammatory and autoimmune diseases.
Zilganersen granted U.S. FDA Fast Track designation for people living with Alexander disease
Zilganersen has been granted Fast Track designation from the U.S. Food and Drug Administration (FDA) for treatment of children and adults with Alexander disease. This helps with the development and expediting the review of medicines that show they have potential to treat serious conditions and unmet need for treatment.
Myrtelle Announces Significant Reduction in N-Acetylaspartate (NAA), a Key Biomarker, in Patients Treated in Its Phase 1/2 Clinical Trial of the Investigational Gene Therapy rAAV-Olig001-ASPA for Canavan Disease
24 months post treatment with rAAV-Olig001-ASPA in the Phase ½ clinical trial has shown decreased N-Acetylaspartate (NAA) (over 80%) from baseline in 7 patients. High levels of NAA have been found in Canavan disease patients due to the deficiency in ASPA enzyme being unable to break down NAA and suggest detrimental effects in the cerebrospinal system. NAA is a neurochemical in the brain that is involved in myelin creation and brain bioenergetics (production and use of energy). Magnetic Resonance Imaging (MRI) showed increased brain white matter and myelin volume in these patients as well. This treatment aims to restore ASPA function thus improving NAA breakdown and myelination.
Research summaries
Adrenoleukodystrophy (ALD)
Lipidomic biomarkers in plasma correlate with disease severity in adrenoleukodystrophy
https://www.nature.com/articles/s43856-024-00605-9
This study investigates the correlation between lipid profiles, particularly the very long chain fatty acid (VLCFA) LPC(26:0) levels, and disease severity in both male and female adrenoleukodystrophy (ALD) patients. The researchers found that increased plasma LPC(26:0) concentrations were strongly associated with more severe disease symptoms, including adrenal insufficiency, cerebral ALD (CALD), and spinal cord disease. Importantly, these associations were consistent across both male and female patients, despite the fact that women tend to develop symptoms later in life. The study also examined X-inactivation patterns in female patients, revealing a strong correlation between skewed X-inactivation toward the ABCD1 pathogenic variant and higher LPC(26:0) levels, which aligns with disease severity. Notably, these findings emphasise the importance of LPC(26:0) in assessing disease progression and its role as a reliable biomarker for diagnosing ALD. Additionally, this highlights its superiority to total VLCFA analysis, as it is less influenced by factors like diet and sampling conditions. In a clinical context, haematopoietic cell transplantation (HCT) significantly reduced LPC(26:0) levels in CALD patients, although not to the levels observed in healthy individuals, demonstrating the treatment’s effectiveness in managing lipid abnormalities in ALD. This study highlights the critical role of targeted LPC(26:0) analysis in both predicting the risk of disease progression and diagnosing ALD, advocating for its wider use in patient management, especially for long-term monitoring and screening. Additionally, the study suggests that LPC(32:0) may serve as an emerging biomarker for ALD, requiring further research. In conclusion, this research underlines the importance of lipidomics and targeted lipid analysis for better understanding the biochemical underpinnings of ALD, offering potential pathways for improved prognosis, diagnosis, and treatment options for patients with ALD.
Adrenal insufficiency and the use of mineralocorticoid treatment in male patients with adrenoleukodystrophy; a retrospective analysis of an institutional database
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382501
Adrenal insufficiency happens when the adrenal glands, located on top of the kidneys, malfunction. Depending on the cell layer affected, adrenal glands do not produce enough of certain steroid hormones. Adrenal insufficiency is one of the signs of adrenoleukodystrophy (ALD) along with cerebral symptoms and is mainly present in the male population. In ALD, the accumulation of very long-chain fatty acids (VLCFA) mostly affects the adrenal layers that make glucocorticoids (regulating glucose metabolism) and androgens (male sex hormones). The production of mineralocorticoids (regulating salt and water) appears less impaired. The present study evaluated the prevalence of male ALD individuals affected by adrenal insufficiency in an American institution. Researchers used Electronic Medical Records (EMR) to look for adrenal insufficiency diagnosis and treatment reports from the history of 358 male ALD individuals. Data showed that 60% of them had a clinical diagnosis of adrenal insufficiency. Among those, 39% received mineralocorticoid replacement therapies. The study concluded on a high prevalence of adrenal insufficiency in the context of ALD, and the need for additional studies to determine the risks for mineralocorticoid deficiency in ALD.
Global Presence and Penetrance of CSF1R-Related Disorder
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11398975
CSF1-Related Disorder (CSF1-RD)is a rare hereditary neurodegenerative disease related to colony-stimulating factor 1 (CSF1) gene mutations. As of February 2024, 199 pathogenic or likely pathogenic variants have been reported across several countries (3 newly reported countries in the present article), and most appear unique to specific families. The CSF1R p.Ile794Thr variant has been detected in 3 distinct families, allowing a more detailed genetic analysis called haplotype analysis. A haplotype is a group of genes that are close together on a chromosome and are often inherited together. Haplotype analysis is used to investigate genetic variation and understand how genes evolve. Here, the analysis indicated a shared haplotype, thus indicating a possible common origin for this variant in 2 of the 3 families. In this article, researchers further detected 8 novel variants among the 15 new patients included in the analysis. While most affected people are heterozygous (when the mutation is only on one of the two versions of the gene), 3 individuals appear compound heterozygous (when both versions of the gene are affected but with a different mutation). Compound heterozygous individuals had an age of onset of 1, 4 and 22 years, respectively, while heterozygous individuals had an average age of onset of 39 years (range 8-71 years). This study also reports 7 symptomatic individuals with no family history of the disease. A mutation carrier’s likelihood of developing the associated clinical condition is called penetrance, environmental and genetic factors can effect it. A negative family history may also be explained by new, non-inherited de novo mutations, or mosaicism in the affected individual’s parents. Mosaicism is when not all body cells contain the same genetic information. Therefore, a mosaic parent could still pass on the mutation despite having no symptoms. In conclusion, this study highlights the global presence of CSF1-RD and its clinical variability. Further research is needed on both symptomatic and asymptomatic individuals to better understand the factors influencing disease variability and better apprehend CSF1-RD care.
Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models
https://www.nature.com/articles/s41467-024-51884-8#Abs1
This study explores the potential of CBD (cannabidiol) as a treatment for Leigh Syndrome (LS), a rare and severe neurodegenerative disorder. CBD, already known for its safety and non-psychoactive properties, showed promise in preventing fatal seizures in mouse models of mitochondrial diseases (MDs), including LS, where conventional epilepsy drugs often fail. Beyond seizure control, CBD demonstrated broad therapeutic effects by reducing oxidative stress and neuroinflammation —two key factors in LS. It increased antioxidant defences like glutathione (GSH) and metallothioneins (MT1/MT2), offering protection to affected cells. This emphasises the multi-targeted action of CBD which can aid LS management to make it more effective than treatments focusing on a single mechanism. Importantly, the benefits of CBD were linked to the activation of PPARγ, a protein involved in regulating cellular processes essential to mitochondrial and immune function. While another drug targeting PPARγ (leriglitazone) also improved outcomes in LS models, CBD was found to be more effective, hinting at the possibility of combining both therapies for enhanced results. The study acknowledges that further research is needed, particularly to confirm CBD’s effects on different LS mutations and mitochondrial functions. However, since CBD is already approved for other rare paediatric conditions, it may offer a faster path to clinical trials for LS. In summary, CBD’s safety, wider therapeutic action, and possibility to tackle LS symptoms offer hope for developing an effective treatment for this challenging disease.
The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381339
Leigh syndrome is a rare brain genetic disorder characterised by dysfunctional mitochondria, the cells’ energy provider. Mutations in the mitochondrial TACO1 gene are one of the disease-causing genetic alterations. They lead to dysfunctional TACO1 protein and are associated with cytochrome c oxidase subunit 1 (COX1) deficiency, a key element for mitochondrial respiration and energy production. This article investigated the relationship between mitochondrial TACO1 impairment and COX1 synthesis reduction. There are two main steps for protein synthesis: transcription (from DNA to RNA) and translation (from RNA to protein). In a cellular model of TACO1 deficiency (TACO1-KO HEK293T), despite increased COX1 RNA levels, researchers observed a reduction in normal COX1 protein synthesis and an increase in truncated forms, suggesting an impairment in the translation of COX1 RNA to protein. Additional protein synthesis experiments (pulse-labelling) showed that translation was correctly initiated but prematurely stopped at various sites. Translation is carried out by molecular units called ribosomes (or mitoribosomes when occurring in the mitochondria). Using 3 different methods (sucrose gradient sedimentation, SILAC, and proximity-biotinylation assay BioID), researchers showed that TACO1 may be involved during the active translation phase via association with mitoribosomes. After analysis of mitoribosomes’ position on RNA, data revealed physiological stalling sites in the COX1 RNA at positions displaying multiple (up to 3) proline motives. Prolines cause ribosomes to pause protein translation because of the rigidity of their conformation and to facilitate the correct folding and insertion of the produced protein into the cell membrane. Data further showed that when TACO1 was absent, translation did not resume after pausing, suggesting that TACO1 alleviates prolonged translation stalling at proline-rich regions in mitochondria. In conclusion, this article highlighted the mechanisms underlying TACO1-related COX1 deficiency and mitochondrial disorders. Nonetheless, additional structural studies are necessary to unravel the precise interaction between TACO1 and the mitochondrial translation machinery.
Anything is better than nothing’: exploring attitudes towards novel therapies in leukodystrophy clinical trials
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378604
Leukodystrophy is a group of rare, progressive neurological disorders and this study explored how people with leukodystrophy and their caregivers feel about participating in clinical trials. Participants expressed a strong desire to join clinical trials, driven by the hope for better outcomes and new treatments. Many felt that the potential benefits outweighed the risks, despite the common occurrence of invasive procedures like lumbar punctures in the trials. Parents, in particular, were motivated by the possibility of helping future children and families. Both adults and caregivers highlighted the importance of trusted doctors in overseeing their decisions about joining trials. They believed that clinician involvement would help them better understand trial risks and provide reassurance. However, concerns were raised about the long timelines of clinical trials, as many feared that treatments might arrive too late due to the fast progression of the disease. Participants also showed preference for trial designs that guaranteed access to the active treatment, rather than placebo. Honesty and transparency from trial recruiters were seen as key to building trust and encouraging enrolment. The study concluded that treating clinicians should be involved in recruitment, compassionate access to investigational treatments should be considered for those who don’t qualify for trials, and timelines should be clearly communicated. Ultimately, while clinical trials offer hope for better outcomes, it is important to balance optimism with realistic communication about timelines and risks to ensure informed decision-making for families and participants.
Concise Articles
GM1 gangliosidosis (GM1), Krabbe Disease, Metachromatic leukodystrophy (MLD)
GEMMABio Announces $100 Million Agreement with Brazil’s Leading Health Research Institute
Metachromatic leukodystrophy (MLD)
Orchard Therapeutics and Er-Kim Announce Partnership to Broaden Access to Libmeldy to Eligible Patients in Turkey and Certain Eurasian Countries