Research summaries – Dec 2020 – March 2021

Download Research Summary Dec 2020 – March 2021

Alex - The Leukodystrophy Charity

A new genetic mutation has been associated with X-linked adrenoleukodystrophy in a Taiwanese family

From the article – by Chien et al (2021)

ALD is caused by mutations in the gene ABCD1, which contains the instructions for making a protein known as ABCD1 (adenosine triphosphate-binding cassette, subfamily D). In this study, researchers in Taiwan describe the symptoms of a male ALD patient who has a mutation in ABCD1 never previously observed in any ALD patient. The patient was found to have increased levels of a type of biological molecule known as ‘very long chain fatty acids’, an observation indicative of ALD. In this article, the researchers discuss in detail something known as ‘genotype-phenotype correlation’. A genotype is a term used to refer to an individual’s genetic identity. In this paper, for example, genotype means the version of the ABCD1 gene a person affected by ALD possesses. A ‘phenotype’ is then the physical manifestation a genotype. In this context, the phenotype is the consequence of the ABCD1 mutation, i.e., the set of symptoms an individual carrying a mutation in ABCD1 experiences. In some conditions, there may be a correlation between genotype and phenotype. For example, patients with mutations in a certain part of a gene may experience more severe disease. However, this is not the case in ALD. Knowledge of where a given mutation occurs in the gene may not be used to predict how severe a disease might be, and individuals with the same mutation may experience different symptoms. The reasons for this are currently unknown, and research into why individuals with the same ABCD1 mutations are affected so differently is ongoing.

Alex - The Leukodystrophy Charity

Using fruit flies to understand neurodegeneration in ALD

From the article ‘Drosophila melanogaster as a genetic system to dissect the mechanisms of disease that lead to neurodegeneration in ALD’ by Bülow et al, 2020

Drosophila melanogaster is the scientific name for a species of small fruit fly commonly used by scientists studying neurological genetic diseases. Despite having huge physical difference to humans, these fruit flies do, in fact, share a large number of the same genes. In addition, the network of nerve cells in the fruit fly brain is organised similarly to those in the human brain. Drosophila melanogaster have been used by scientists for decades in genetic experiments, and as a result, there are a large number of tools and techniques available which researchers can use to manipulate their genes. It is possible, for example, to introduce a mutation into the fruit fly equivalent of the gene linked to ALD development, ABCD1. The fly will then develop a condition which mirrors human ALD, and scientists can study how the mutation affects neuronal function at the cellular level. Although there are certainly limitations to how much studies in fruit fly can reveal about the mechanism of disease in humans, a number of important discoveries have been made in Drosophila melanogaster by scientists studying Parkinson’s Disease.

Alex - The Leukodystrophy Charity

Viking Therapeutics Inc. and clinical trials of VK0214 for the treatment of X-linked ALD

Viking Therapeutics is currently carrying out a Phase 1 clinical trial of a drug designed to treat X-linked ALD, VK0214. VK0214 is designed to compensate for mutation and loss of function of ABCD1, genetic mutations in which are responsible for ALD. VK0214 works by increasing the expression of a related gene, ABCD2. ABCD2, like ABCD1, contains the instructions for a protein which functions to degrade a class of biological molecule known as ‘Very Long Chain Fatty Acids’ (VLCFA). In the absence of either ABCD1 or ABCD2, the VLCFA accumulate to toxic levels and cause damage to the central nervous system (the brain and spinal cord). Phase 1 clinical trials are designed to make sure that the new medicine presents no major safety issues, that the drug will reach the intended area of the body and remain there sufficiently long enough to deliver a benefit, and to gain some evidence that the drug has a therapeutic effect. The trial of VK0214 aims to establish not only the safety and tolerability of the drug, but to identify proper doses which can be used in later trials with ALD patients. Viking Therapeutics hopes to publish data from their Phase 1 trial later in 2021, and initiate Phase 1b trials in mid-2021. These Phase 1b trials will be the first stage of assessing the effect of VK0214 in patients affected by X-ALD. Although still in an early stage of development, VK0214 represents a promising therapeutic approach for the treatment of X-ALD.

Alex - The Leukodystrophy Charity

Minoryx presents results from a Phase 2/3 trial demonstrating benefit of leriglitazone in adrenomyeloneuropathy.

Minoryx Therapeutics, a biotech company focussed on the development of therapeutics for disorders of the central nervous system (CNS), have recently announced results from a Phase 2/3 clinical trial of leriglitazone for the treatment of adrenomyeloneuropathy (AMN) in male patients. The clinical trial was conducted on 96 patients over approximately 2 years, and it was found that early-symptomatic AMN patients who received leriglitazone experienced a clinically meaningful difference in the ability to complete a ‘6-minute walk test’ compared to patients who received a placebo. In addition, patients who received leriglitazone also did well on the ‘sway test’, which together with the results of the walk test indicate reduced loss of control of balance and body posture. These patients also experienced reduced progression on both the Expanded Disability Status Scale and the Severity Score System for Progressive Myelopathy compared to patients who received placebo. Leriglitazone treatment also had the effect of reducing the progression of cerebral lesions. Following the trial, around 90% of patients elected to keep taking the treatment, and data will continue to be collected.

This study by Minoryx Therapeutics demonstrates promise for the use of leriglitazone for the treatment of AMN, and the company is currently preparing for discussions with regulatory authorities regarding how AMN patients can gain access to this drug in future.

Alex - The Leukodystrophy Charity

Symptoms of Multiple Sclerosis and CADASIL may overlap

From the article ‘A Case of Atypical Multiple Sclerosis Mimicking Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Syndrome’ by Varoglu et al, 2021

CADASIL (which stands for ‘Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy’ is a rare, inherited type of vascular dementia. This means that CADASIL patients experience memory loss, confusion, behaviour and personality changes due to the presence of a genetic mutation in a gene known as ‘NOTCH3’. The NOTCH3 gene carries instructions for the protein NOTCH3 (Neurogenic locus notch homologue protein 3), which plays an important yet not entirely understood role in the central nervous system (the brain and spinal cord). CADASIL patients also often experience migraine and strokes in a particular region of the brain. In the past, several patients who were previously given a diagnosis of multiple sclerosis were later found to have CADASIL, as a number of symptoms are common between the two conditions. In the scenario described in this article, however, the reverse was found, and a patient with MRI results consistent with a CADASIL diagnosis was in fact found to have multiple sclerosis. Despite the MRI results indicating CADASIL, the patient did not have a mutation in the NOTCH3 gene, nor were they affected by the classical CADASIL symptoms of dementia and migraine. The patient was responded positively to a type of anti-inflammatory therapy. The researchers who conducted this study conclude that, for patients in whom a diagnosis of either CADASIL or multiple sclerosis is being considered due on the basis of MRI results, it may be useful to take into account wider clinical symptoms and the treatment to which a patient is responding. Neurological conditions such as CADASIL and multiple sclerosis are extremely complex, and patients affected by each condition often experience symptoms on a spectrum. The authors of this article suggest the possibility that they have identified a new variant of either multiple sclerosis or CADASIL, or that the patient described in this paper is affected by both conditions. Further research regarding how best to distinguish between multiple sclerosis and CADASIL is needed, but this study will provide a useful case study to future doctors and researchers attempting to understand which treatment and diagnosis to give patients affected by the same symptoms and scan results described in this paper.

Alex - The Leukodystrophy Charity

Diagnosis and treatment of Cerebrotendinous Xanthomatosis (CTX)

From the article ‘Cerebrotendinous Xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid’ by Islam et al, 2021 Cerebrotendinous Xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid | Cerebellum & Ataxias | Full Text (

Cerebrotendinous Xanthomatosis (CTX) is a rare condition caused by mutations in the gene CYP27A1. This gene contains instructions for making the protein CYP27A1, which is required for bile acid production. Bile acids have numerous functions in the body, but are principally needed for aiding in the digestion of dietary fats and helping to eliminate cholesterol from the body. When CYP27A1 does not function properly, a chemical known as ‘cholestanol’ accumulates and causes damage to various bodily tissues, including the eyes, part of the brain and tendons. CTX is a serious disorder. However, it is treatable, with best results achieved when the condition is identified as early as possible. This is complicated by the fact that CTX can manifest in diverse ways, with even affected identical twins experiencing different symptoms. Typical symptoms of CTX include: infantile-onset diarrhoea, childhood and juvenile onset cataracts, tendon xanthomata (nodules which form under the skin over tendons, usually the Achilles tendon and in the hands and feet), and either childhood or adult-onset neurological problems. These symptoms may occur in CTX patients to varying degrees and in varying combinations. This article describes the experience of four patients affected by CTX in detail, including both their current and historical symptoms, and the treatments they have received/are receiving. All four patients had extremely different experiences of CTX, and between them had a median age of diagnosis of 39 years, despite some having had symptoms since childhood. Typically, CTX is diagnosed based on the presence of early-onset cataracts, tendon xanthomata and progressive ataxia (uncoordinated movement and speech). However, in the patients described in this paper, this ‘triad’ of symptoms was only present in one out of the four individuals. Unlike many complex conditions affecting the central nervous system, CTX is treatable, with administration of chenodeoxycholic acid (CDCA) being able to either reverse, stabilise or slow the progression the of the disease. Based on the descriptions of the first symptoms reported by the patients described in this paper, the authors conclude that when considering a diagnosis, spastic paraparesis (partial paralysis of the lower limbs), early-onset cataracts, and behavioural/cognitive problems more typically associated with autism spectrum disorders should be considered indicative of CTX, and cholestanol levels in both the blood and cerebrospinal fluid should tested as part of the diagnostic workup. Moving forward, the increased availability of genetic testing should also facilitate earlier diagnosis of CTX.

Alex - The Leukodystrophy Charity

The first patient has been treated in a clinical trial of a gene therapy for Tay-Sachs and Sandhoff Disease

GM2 gangliosidosis is caused by mutations in one of two genes which contain the instructions for making the protein ‘beta-hexosaminidase A’. This protein is responsible for breaking down other proteins in a subcellular structure known as a ‘lysosome’, which may be thought of as a sort of ‘recycling centre’ for the cell. People in whom beta-hexosaminidase A does not function correctly as a result of these genetic mutations experience a variety of neurological symptoms as cellular proteins are not broken down correctly and build up to toxic levels in the brain. Beta-hexosaminidase A is composed of both an ‘A’ and ‘B’ subunit, the instructions for which are contained in two different genes. Depending on whether the mutation occurs in the ‘A’ gene or ‘B’ gene, GM2 can also be known as either Tay-Sachs or Sandhoff disease. The fact that Tay-Sachs and Sandhoff disease are each caused by mutations in single genes makes them amenable to gene therapy; a type of therapy in which a modified virus is used to deliver ‘corrected’ versions of the A and B beta-hexosaminidase genes into a patient. This press release from the pharmaceutical company Sio Gene Therapies Inc reports that the first patient with infantile-onset Tay-Sachs disease has been dosed in a Phase 1/2 clinical trial designed to test how well a GM2 gangliosidosis gene therapy works. The therapeutic is known as AXO-AAV-GM2, and is the first ‘disease-modifying’ treatment for GM2 gangliosidosis, meaning it has potential to slow, stop or potentially even reverse the progression of disease. Up until now, the only treatments available are those designed to help manage symptoms. This trial will, in the first stage, assess safety and the most effective dosing regiment for AXO-AAV-GM2. The second stage will involve further evaluation of safety and how effective the treatment is. Although much further work is needed to determine how effective AXO-AAV-GM2 will be at treating GM2 gangliosidosis, results from previous ‘expanded access’ clinical studies indicates that it will be both well-tolerated in patients and associated with good clinical outcomes.

Alex - The Leukodystrophy Charity

Polaryx Therapeutics receives both ‘Rare Paediatric Disease’ and ‘Orphan Drug’ designations for the treatment of Krabbe disease with PLX-300

A recent press release reports how a treatment developed by Polaryx Therapeutics for Krabbe disease has received both Rare Paediatric Disease and Orphan Drug designations from the US Food and Drug Administration (FDA). Krabbe disease is an extremely rare condition caused by mutations in a gene which carries instructions for the cellular protein ‘galactocerebrosidase’ (GALC). When GALC does not function correctly, levels of a biological chemical known as galactosylsphingosine build up to toxic levels in the brain and spinal cord, causing nerve damage and neurodegeneration. Krabbe disease is a serious condition affecting young children, who usually pass away from the disease before the age of two. Unlike many new treatments which are being designed and tested for the treatment of leukodystrophies, PLX-300 is not a type of gene therapy, but is in fact a ‘small molecule drug’ which is otherwise frequently found in food flavouring or as a spice (the term ‘small molecule drug’ is often used by pharmaceutical companies to refer to any ‘small molecule’ which has biological activity’. It has been found that PLX-300 can stimulate the expression of other genes (and therefore the production of other cellular proteins) which may go some way to compensate for the loss of GALC function, restoring normal galactosylsphingosine degradation. The Rare Paediatric Disease designation that Polaryx has received for PLX-300 means that if approved, the drug will be eligible for priority review. Expedited review and approval are also associated with the FDA Orphan Drug designation. Altogether, this means that PLX-300 is likely to enter clinical trials sooner than would have been the case, if the treatment had not been developed to treat such a rare and life-limiting disease affecting young people.

Alex - The Leukodystrophy Charity

Orchard Therapeutics reports progress in various clinical and non-clinical studies regarding treatment and benefit of gene-therapy approaches for leukodystrophies, as well as identification and early-diagnosis strategies


Orchard Therapeutics, one of the world leaders in gene therapy, have announced new data from a number of studies at this year’s WORLDSymposium conference demonstrating the benefit of gene therapeutic approaches for the treatment of several genetic conditions affecting the central nervous system (the brain and spinal cord).

Firstly, researchers at the TIGET institute in Italy working in collaboration with Orchard Therapeutics have found that patients affected by a subtype of MPS-I (also known as Hurler, Hurler-Scheie and Scheie syndrome) may benefit from a treatment known as OLT-203. Indeed, the majority of individuals to whom OTL-203 was administered in a clinical study experience no cognitive decline or deterioration in motor function over at least a 12-month period. Similarly, a study in three patients which aimed to assess the use of the treatment OTL-201 for treatment of Sanfilippo syndrome Type A (or MPS-IIA) has yield promising results. Evidence of expression of the ‘corrected’ version of the gene associated with Sanfilippo syndrome was found in all three patients, with concomitant changes in the levels of several biomarkers associated with the disorder (biological signs of the disease which scientists and clinicians use to monitor disease progression and treatment responses).

At the WORLDSymposium in February, Orchard Therapeutics also presented information regarding their metachromatic leukodystrophy (MLD) patient identification strategy. By poster presentation, Orchard Therapeutics reported on the language and words which parents and caregivers typically use to describe the first symptoms of MLD. It is thought that increased awareness of this will aid clinicians in the diagnosis of the condition. Orchard Therapeutics also reported results from a prospective newborn screening strategy in northern Germany, including details of the methodology used to conduct the screening and which biomarkers of MLD were being analysed. In addition, data outlining the impact on quality of life of MLD on both patients and caregivers was presented. By assessing this measure, Orchard Therapeutics will be more easily understand the overall value of the treatment they are developing for MLD, Libmeldy (otherwise known as OTL-200). In parallel, the annual healthcare resource utilisation (HCRU) associated with managing and treating MLD patients in the NHS was described. As with quality-of-life assessments, HCRU will allow for a deeper understanding of the overall benefit of Libmeldy, and is a measure that Orchard Therapeutics will use to support discussions regarding Libmeldy access for MLD patients across Europe and beyond. Finally, Orchard Therapeutics took the opportunity at the WORLDSymposium to deliver an update on clinical studies assessing the benefit of this treatment, Libmeldy, for MLD patients. Libmeldy has been approved by the European Commission for the treatment of MLD in eligible patients (those with early juvenile disease who can still walk independently and have no yet developed mental deterioration, and those with late-infantile or early-juvenile forms of the disease who have not yet developed symptoms), with some patients to whom Libmeldy was administered continuing to experience benefits up to 8 years after treatment in previous, initial clinical studies.

Indeed, data presented at this conference confirm that the effects of Libmeldy are both durable and clinically relevant. This means that there is tangible benefit for MLD patients who were treated with Libmeldy prior to moving into the rapidly progressive phase of the disease. Libmeldy is not a perfect treatment; indeed, despite administration of the treatment, two patients in the group did not survive, and one patient who was treated during a phase of rapid disease progression experienced deterioration in their motor function. However, it remains that 5/6 patients treated in this group retained normal cognitive development and were able to sit without support in the second year following treatment with Libmeldy, giving promise to the potential use of this therapeutic for effective MLD treatment

Alex - The Leukodystrophy Charity

Investigational New Drug application for a potential gene therapy treatment for Krabbe Disease

This press release is an announcement from Passage Bio, Inc., a biotechnology company focussed on developing gene therapeutics for the treatment of central nervous system disorders, that an ‘Investigational New Drug’ (IND) application for the gene therapeutic PBKR03 has been cleared by the US Food and Drug Administration (FDA). PBKR03 has been developed for the treatment of early-infantile Krabbe disease, a rare and severe neurological disorder caused by mutation in a gene known as GALC. This gene contains the instructions for a protein (also known as GALC), which when either absent or incorrectly functioning leads to accumulation of a biological chemical that causes damage to nerve cells, causing neurodegeneration. PBKR03 functions to deliver a ‘corrected’ version of the GALC gene into patient cells using a harmless virus ‘vector’, which in theory will restore normal function of the protein encoded by GALC, thus preventing neurodegeneration. PRKR03 has been studied extensively in pre-clinical (laboratory) models; for example, mice which have been engineered to develop symptoms similar to those experienced by human Krabbe disease patients, with promising results obtained. The recent IND status awarded to Passage Bio by the FDA is confirmation that the pre-clinical studies have shown that the treatment will likely be safe, and will allow clinical trials to begin. The IND will, for example, allow the company to ship the treatment across state lines to begin testing in hospitals and institutions across the US. Passage Bio expects to initiate a phase 1/2 clinical trial examining the safety, correct dosing schedule and efficacy of PBKR03 in the first half of 2021, with initial data expected either late 2021, or early 2022.

Alex - The Leukodystrophy Charity