Category: Leukodystrophy

Florian Eichler, M.D., Christine Duncan, M.D., Patricia L. Musolino, M.D., Ph.D., Paul J. Orchard, M.D., Satiro De Oliveira, M.D., Adrian J. Thrasher, M.D., Myriam Armant, Ph.D., Colleen Dansereau, M.S.N., R.N., Troy C. Lund, M.D., Weston P. Miller, M.D., Gerald V. Raymond, M.D., Raman Sankar, M.D., Ami J. Shah, M.D., Caroline Sevin, M.D., Ph.D., H. Bobby Gaspar, M.D., Paul Gissen, M.D., Hernan Amartino, M.D., Drago Bratkovic, M.D., Nicholas J.C. Smith, M.D., Asif M. Paker, M.D., Esther Shamir, M.P.H., Tara O’Meara, B.S., David Davidson, M.D., Patrick Aubourg, M.D., et David A. Williams, M.D.– 2017

Wolfgang Köhler, Marc Engelen, Florian Eichler, Robin Lachmann, Ali Fatemi , Jacinda Sampson, Ettore Salsano, Josep Gamez, Maria Judit Molnar, Sílvia Pascual, Maria Rovira, Anna Vilà, Guillem Pina, Itziar Martín-Ugarte, Adriana Mantilla, Pilar Pizcueta, Laura Rodríguez-Pascau, Estefania Traver, Anna Vilalta, María Pascual, Marc Martinell, Uwe Meya, Fanny Mochel, and the ADVANCE Study Group – 2023

A clinical trial carried out in several countries has just been completed. Although it has not shown a favorable effect on adrenomyeloneuropathy, it provides interesting information for the treatment of cerebral adrenoleukodystrophy. Indeed, no patient who received the drug developed brain damage during the trial, unlike the men in the placebo group.

Most adults with the adrenoleukodystrophy gene develop adrenomyeloneuropathy, a chronic myelopathy which usually begins before the age of 30. Adrenomyeloneuropathy is characterized by severe and continuous axonal damage in the central and peripheral nervous system, and in particular causes stiffness when walking and balance disorders.

Cerebral adrenoleukodystrophy (cALD) is an aggressive inflammation of the brain. It affects 30 to 40% of boys aged 4 to 8 born with an ABCD1 gene mutation. Men with adrenomyeloneuropathy also develop cerebral adrenoleukodystrophy for more than half of them.

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial

Wolfgang Köhler, Marc Engelen, Florian Eichler, Robin Lachmann, Ali Fatemi, Jacinda Sampson, Ettore Salsano, Josep Gamez, Maria Judit Molnar, Sílvia Pascual, Maria Rovira, Anna Vilà, Guillem Pina, Itziar Martín-Ugarte, Adriana Mantilla, Pilar Pizcueta, Laura Rodríguez-Pascau, Estefania Traver, Anna Vilalta, María Pascual, Marc Martinell, Uwe Meya, Fanny Mochel, and the ADVANCE Study Group

Background

Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.

Methods

ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.

Findings

Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: −27·7 [41·4] m; placebo: −30·3 [60·5] m; least-squares mean difference −1·2 m; 95% CI −22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.

Interpretation

The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.

Funding: Minoryx Therapeutics

Reference : Köhler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M.J., Pascual, S., et al. (2023). Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. Lancet Neurol. 22, 127–136

The Families/Researchers meeting took place online on April 6^th and 7^th 2024 afternoon

With a simultaneous translation in 5 languages (German, English, Spanish, French, Italian, Czech) this meeting was open to the international community of patients concerned by leukodystrophy and once again gives the opportunity to gather around researchers from around the world.

Discover the whole meeting Families/Researchers

Krabbe leukodystrophy (KD) is a progressive and fatal neurologic lysosomal storage disorder that usually affects infants and causes death before two to three years of age. Hematopoietic Stem Cell Therapy extends the long-term survival with improved quality of life for KD patients, but it is not a cure. Using our newly developed KD animal model, we will identify which brain cell(s) needs to be efficiently cured with therapy.

Project financed by ELA up to:  71 082 €

Metachromatic Leukodystrophy (MLD) is a rare demyelinating disease, due to arylsulfatase A (ARSA) deficiency, an enzyme involved in the catabolism of sulfatides, the main component of the myelin sheath. This deficiency leads to progressive demyelination of central nervous system and peripheral neuropathy. The most frequent form of the disease is the late infantile form of the disease which is characterized by a rapid progression of the disease, especially after the first onset of symptom. Ex vivo gene therapy develop by the group of Alessandra Biffi, and based on engraftment of lentiviral transduced hematopoietic stem cells has been shown to be effective for presymptomatic forms of MLD but not effective in early symptomatic patients, probably due to the rapid evolution and the time needed for the engrafment. On the other hand, enzyme replacement was shown as potentially effective but needed a chronic delivery. In the group, we previously proposed a gene therapy approach for MLD based on intracerebral delivery of an AAVrh.10 encoding ARSA. We had established proof of concept in mouse model of the disease and scale up study in non-human primates (NHP) leading us to propose a clinical trial which included 4 patients from 2013 to 2016. Despite ARSA expression in the brain and detection in cerebrospinal fluid (CSF) we failed to obtained any therapeutical benefits in these patients. Our point is that expressing ARSA in the CNS is fundamental to rapidly stop the disease progression, however, it could be essential also to bring back in patient healthy microglial cells. This project aim at establishing the proof of concept of rapid, sustained and important ARSA expression in the whole CNS (brain, spinal cord) and potentially also in the peripheral nerve. To achieve this aim, we propose to use a novel serotype of AAV: AAVPHP.eB that has been engineered to efficiently cross the blood brain barrier (BBB) after IV delivery. The project will be divided in two main parts, first a rapid study in the MLD mouse model both for pre and post symptomatic treatment, in order to evaluate efficiency of AAVPHP.eB-ARSA vector for biodistribution, ARSA expression, sulfatides correction, Purkinje cell prevention and behavioral testing. In a second phase, we want to test this vector in NHP thought several routes of delivery: intravenous (IV), intrathecal (IT) and intracerebroventricular (ICV), especially by potential coupling of these routes of administration to optimize CNS targeting. This with the final aim to propose a clinical trial for symptomatic MLD patients.

Project financed by ELA up to: 100 000 €

Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) is a leukodystrophy caused by defective cytoplasmic Aspartyl-tRNA synthetase (DARS). This enzyme is involved in building proteins, a fundamental biological process in bacteria and man alike. HBSL is caused by autosomal recessive mutations in the DARS gene and all point mutations identified result in neurological disease. HBSL is a potentially fatal spectrum disorder with no treatment and unclear etiology. In a pioneering effort our team at the University of New South Wales has generated the first mouse model of HBSL by introducing the same mutations causing HBSL in patients into the mouse Dars gene. Accurate animal models are the prerequisite to study the disease mechanisms and to develop and test treatments. Moreover, we have already identified that DARS expression in the brain of both mouse and man is enriched in neurons with far less expression in glia. This suggests that neurons might be the cells that a first line HBSL therapy should ideally target. In the first aim of this research proposal, we plan to engineer more mouse models that genetically mimic HBSL mutations and characterize them in order to model different forms of severity of HBSL. The second aim will be to develop a gene therapy platform for expression of a healthy copy of the DARS gene in mice. These experiments will help to identify the optimal route of delivery and the best timing for intervention. In the third aim we will perform a proof-of-concept gene therapy in the most relevant mouse model using optimized paramemters for DARS gene therapy identified in the previous aims. This project will yield an accurate animal model of HBSL that will be instrumental for preclinical testing of gene therapy or other treatment avenues. We propose that this study will generate data with high clinical relevance as our preclinical endpoints and gene therapy platform could easily be adapted for the treatment of other leukodystrophies caused by abnormal protein translation.

Project financed by ELA up to: 97 575 €

4H syndrome, an inherited brain white matter disorder (leukodystrophy), leads to considerable clinical handicap, ranging from mild to severe. Most patients deteriorate over time. There is no treatment yet, and we do not understand what goes wrong in the brain. There are no good animal models for this disease, hampering research. We think that besides white matter and myelin, also the nerve cells (neurons, also called grey matter) and their processes (axons) are damaged from early disease stages on. In our project, we want to explore this grey matter involvement with an innovative approach.

We are able to make white and grey matter cells from 4H patient and control fibroblasts. Earlier studies showed that 4H patient cells show affected expression of genes involved in nerve cell development. As nerve cells provide signals to white matter cells and myelination, neuronal defects could underlie abnormalities found in grey and white matter areas in 4H patient brains. We want to study co-cultures of both grey and white matter cells derived from patient cells to know how they influence each other. In the future, this might be a good model for drug screening to treat 4H.

Project financed by ELA up to: 99 565 €

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder characterized by an abnormal head, loss of motor functions, epilepsy and mild mental decline. The disease is caused by mutations in two genes named MLC1 and GLIALCAM. There are no therapies for MLC patients, only palliative treatment. Interestingly, some patients with GLIALCAM mutations show a remitting phenotype, suggesting that it may be possible to improve the phenotype of MLC patients, even at later stages of the disease.

We present here a gene therapy preclinical therapeutic approach for MLC patients using two animal models of the disease, the Mlc1 and the GlialCAM knock-out mice. Therapeutic genes will be delivered by one-time treatment to the CNS, overcoming the difficulty of crossing the blood-brain barrier. We hope that the results of this project will be able to provide the first therapeutic tools for patients affected with MLC and may have also implications to treat other diseases affecting the myelin.

Project financed by ELA up to: 57 600 €

X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy with the adult-onset peripheral nerve disease adrenomyeloneuropathy being the underlying core syndrom. However, the majority of patients also develop fatal inflammatory brain demyelination, termed cerebral ALD (CALD). Hematopoietic stem cell transplantation (HSCT) is an established treatment that is able to halt CALD in both childhood and adult patients and is currently, next to hematopoietic stem cell gene therapy (HSCGT), the only available life-saving intervention for CALD patients. Unfortunately, both HSCT and HSCGT are only effective during a narrow therapeutic window at the beginning of CALD, thus excluding patients with advanced CALD from these treatments. We propose to validate pharmacological compounds known as histone deacetylase (HDAC) inhibitors, which are well-tolerated anti-cancer drugs, as a means to stop the macrophage-related inflammatory responses, with a potential ultimate application for advanced CALD patients. We will compare and evaluate the dosage and ability of three different HDAC inhibitors to reverse functional abnormalities like pro-inflammatory activation and accumulation of very long-chain fatty acids in macrophages isolated from the blood of X-ALD patients. X-ALD macrophages are the immune cells most affected by X-ALD and thus, are therapeutic targets. We think that if HDAC inhibitors prove to be effective in X-ALD macrophages, these drugs might delay, ameliorate or even halt the cerebral inflammation in patients with CALD.

Project financed by ELA up to: 66 315 €