Category: Clinical trial

Pelizeus-Merzbacher’s disease (PMD) is an inherited disease affecting the central nervous system characterized by physical and mental impairment. In the majority of cases, PMD is due to an increase in the expression of the PLP1 gene (gene encoding Protein Proteolipid 1 or lipophilin, the primary constituent of myelin). Currently, there is no cure for patients with PMD.

As part of an experimental therapeutic approach, we were able to reduce the gene expression of PLP1. We have been able to improve the course of the disease by administering an experimental progesterone receptor antagonist in mice mimicking the most common form of PMD.

In order to facilitate the application of our results to patients with PMD, we will attempt to answer the following questions in PMD mice:

Do progesterone antagonists currently authorised in other indications reduce PLP1 gene expression?

How can we optimise the treatment to obtain the best possible therapeutic effects?

What is the long-term impact of treatment acting on the progesterone receptor?

Can we identify other potential classes of drugs that reduce the expression ofPLP1?

RNA polymerase III leukodystrophy (POLR3-HLD), also known as 4H leukodystrophy, is a hypomyelinating leukodystrophy resulting in a spectrum of neurological and extra-neurological manifestations with an age of onset typically in early childhood. Several leukodystrophies described in the 2000s are now grouped under this leukodystrophy since they have similar clinical characteristics and are caused by mutations in the same genes: the 4H syndrome (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism), ADDH (Ataxia, Delayed Dentition and Hypomyelination ), TACH leukodystrophy (Tremor-Ataxia with Central Hypomyelination ), leukodystrophy with oligodontia and HCAHC syndrome ( Hypomyelination with Cerebellar Atrophy and Hypoplasia of the Corpus Callosum ).

A large study on more than 100 patients has allowed us to better understand the spectrum of this disease.

The neurological clinical features of POLR3-HLD include:

significant cerebellar manifestations (ataxia or problem with balance, dysarthria or difficulty pronouncing words correctly, dysmetria  or imprecision of movements), with or without tremor, pyramidal manifestations such as spasticity ( stiffness) and brisk reflexes, as well as so-called extra-pyramidal dystonia-like manifestations (stiffness in the arms and legs, which fluctuates with associated abnormal emotions and postures). Non-neurological features of the disease include:

• dental abnormalities (examples: small teeth, missing teeth, delayed eruption of teeth abnormalities in the order of tooth eruption, etc.),
• eye abnormalities (myopia),
• endocrine abnormalities (example: small size) and pubertal abnormalities (puberty arrest or absence of puberty). POLR3-HLD is caused by recessive mutations in the POLR3A and POLR3B genes. To date, more than 100 patients with this disease have mutations in one or the other of these genes. The POLR3A and POLR3B genes encode the two largest subunits of an enzyme called RNA polymerase III, and together form the active center of the 17-subunit complex. No patient has two null mutations, that is, two mutations that would result in the complete absence of the protein for which the gene codes. This is not surprising given the essential role of RNA polymerase III: the transcription of DNA encoding small RNAs such as transfer RNAs, 5S, U6 and 7SK. These small RNAs are important for the survival of the cell.

Work has begun on the link between mutations in the POLR3A or POLR3B / hypomyelinating leukodystrophy gene. The representation of the mutations found on three-dimensional modeling of polymerase III suggests that the mutations may have an effect on the assembly of the enzyme by altering the interactions between the subunits, or even have an effect on the binding of DNA with the complex, thereby resulting in abnormal transcription of DNA into RNA.

Preliminary results suggest that, at least for one mutation, the first hypothesis seems correct, that a mutation in the POLR3A gene leads to deficient assembly of the complex and, in this case, to migration failure of the complex in the nucleus of the cell, where the polymerase does its job.

Our hypothesis is that mutations in POLR3A or POLR3B lead to an abnormal transcription of certain RNAs, such as transfer RNAs, important for the development of myelin (myelination). We have set up several types of experiments to study these small RNAs from fibroblasts (skin cells from patients and healthy controls) and it seems that there are small variations in the transcription of some RNAs. However, as the skin was unaffected in our patients, and now having mice with mutations in POLR3A, we will now repeat these experiments with myelin and gray matter from diseased mouse brains.

Note that the involvement of transfer RNAs is also suspected in other hereditary diseases involving the cerebral white matter such as LBSL (Leukoencephalopathy with Brainstem and Spinal cord involvement and Lactate elevation) and in two other hypomyelinating leukodystrophies called HBSL ( Hypomyelination with brainstem and spinal cord abnormalities and leg spasticity) and RARS-associated hypomyelination, caused by mutations in the DARS and RARS genes, respectively.

Finally, we have now started the experiments in POLR3A mice, exhibiting motor difficulties. We are going to study its characteristics, its brain. This will allow us to advance our understanding of the pathophysiology of the disease.

The discovery of the associated POLR3-HLD genes has enabled many patients and their families to obtain molecular diagnosis and appropriate genetic counseling. Clinical, radiological, and pathophysiological studies are still ongoing in order to better understand the extent of clinical and radiological manifestations, genetic abnormalities and of course, the pathophysiology of this group of diseases in order to be able to develop therapeutic strategies.

The development of high throughput sequencing (Next Generation Sequencing, NGS) in the 2000s marked a major turning point in genome studies. Exome technology makes it possible to sequence all exons in the genome. The exon is the part of the gene that is translated into proteins. Leukodystrophies are a group of genetic diseases that affect white matter and primarily its major component, myelin. Despite advances in gene identification, 60% of patients remain without any genetic abnormalities found. We performed exome sequencing in a cohort of 80 patients with leukodystrophies of undetermined cause.

We have identified the causal mutation in 56% of cases, the remaining 44% are being analyzed with several candidate variants. This analysis allowed us to divide our cohort into three subgroups. A group with mutations in known genes for leukodystrophies (15%), a 2nd group with mutations in genes already involved in another genetic disease and with a very atypical clinical picture (9%), and a 3rd group with mutations in potentially candidate genes (32%).

The identification of mutations in known leukodystrophy genes by exome sequencing has demonstrated the major interest in developing a chip that brings together all known leukodystrophy genes for diagnostic application.

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

Marjo van der Knaap – 2021

The disease

CACH (Childhood Ataxia with Central Nervous System Hypomyelination) is a rare genetic disease of the hypomyelinating leukodystrophy family, also known as leukoencephalopathy with vanishing white matter (VWM). It is characterised by a progressive degradation of the white matter in the brain, leading to various cognitive disorders and muscle stiffness. These disorders may go unnoticed at first, making early diagnosis difficult. When suspicion is high, the diagnosis can be confirmed by genetic testing. The disease often manifests itself in early childhood, but some patients do not show symptoms until adulthood. There is currently no treatment, only symptomatic treatment is offered for the treatment.

Hope for families

Research teams have been working for years to speed up diagnosis, understand the mechanisms of the disease, find new markers, move towards new therapies, and improve patient management.
Marjo van der Knaap’s team at the VUmc (Center for White Matter Disorders of the VU University Medical Center in Amsterdam, the Netherlands) has been interested in leukodystrophies, but also specifically in CACH syndrome for several years. The gene associated with this disease was identified by the team in 2001 and for the past 20 years, with the support of ELA, researchers have focused on understanding the mechanisms of the disease. As a result of this research, a promising molecule has been identified that could improve the condition of these patients. This molecule, guanabenz, has been marketed for many years in the United States and Europe for the treatment of hypertension in adults. It acts on the cellular stress response (cell defence mechanism) which is involved in CACH syndrome.
The team of researchers led by Marjo van der Knaap ([email protected]) has set up a clinical study with the aim of testing the effectiveness of the molecule in the disease as quickly as possible.

Who can take part in the trial?

A patient is eligible for participation in the trial if he/she meets the following criteria:

• genetically proven VWM
• brain MRI abnormalities consistent with VWM
• at the time of study entry, a maximum disease duration of 8 years
• VWM disease started before the age of 6 years
• able to stand up and walk at least 10 steps, with or without some support
• not suffering from another significant disease (eg, heart, liver or kidney disease)
• not participating in another medical-scientific study
• able to undergo MRI examination (ie, no presence of metal-containing implants, such as cochlea implant, neurostimulator or pacemaker)
• living within reasonable travel distance from Amsterdam

• When all of these eligibility criteria are met, we can start the process of evaluating whether the child can participate in the trial.

Parents/guardians or treating physicians can contact the clinical team at [email protected] to discuss whether a child can participate in the trial.

ELA International is supporting this trial and is contributing €500,000. This study has been open since 1 June and will be conducted for at least one year. It may be extended to 3 or 4 years depending on the progress of recruitment, which is expected to reach 20 patients.

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By supporting clinicians and researchers working on leukodystrophies, ELA is once again involved in the development of international research. Research must continue to improve the understanding of the disease and to develop specific treatments. This first clinical trial on CACH represents real hope for these patients and their families.

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