Research Summary: October 2021

Research summary of recent leukodystrophy research and clinical trails for October 2021, includes summaries and direct links:

Full Research Summaries

ALD

Analysis of brain MRI scans in pre-symptomatic X-ALD patients can be used to predict disease course and inform treatment options

From the paper ‘A Longitudinal Analysis of Early Lesion Growth in Presymptomatic Patients with Cerebral Adrenoleukodystrophy’ by Mallack et al (2021) – access: http://www.ajnr.org/content/early/2021/09/09/ajnr.A7250 

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations the gene ABCD1, which carries the instructions for making a cellular protein of the same name. Any number of mutations in ABCD1 may disrupt the function of the protein ABCD1. However, it isn’t possible to correlate the effect of a given ABCD1 mutation with the course of disease a person affected by X-ALD will experience. In research, this is known as a genotype-phenotype correlation (i.e., the influence a gene or a genetic mutation has on a person’s physical health).

There are several subtypes of X-ALD, and being able to distinguish between these subtypes at an early stage is extremely important, as it influences the treatment plan. Most people with ABCD1 mutations develop cerebral adrenoleukodystrophy (CALD). The majority of these patients experience a progressive form of CALD, which unfortunately has a poorer prognosis than ‘arrested CALD’. In arrested CALD, a person will undergo ‘spontaneous arrest of disease’, meaning symptoms cease to advance in the absence of medical intervention. Patients with arrested CALD are not suitable candidates for haematopoietic stem cell transplantation (i.e., a bone marrow transplant). This procedure, although it does have the potential to improve the symptoms of CALD in certain patients, is not without risk and is associated with significant and serious side effects. For those patients for whom a bone marrow transplant could be of benefit, the procedure is most successful when initiated before the onset of neurological symptoms. It has more recently been shown that alternative gene therapy treatment approaches are more effective when the patient is younger too. As it not possible to use genetic analysis (i.e., the nature of the mutation in ABCD1) to predict how CALD will progress, the researchers in this study have attempted to investigate if there is utility in using the results of brain MRI scans.

Specifically, the aim of this study was to investigate how the results of brain MRI scans changed over time (longitudinally) in patients with CALD, starting from when these patients were pre-symptomatic. This study was carried out retrospectively, meaning the researchers used existing MRI records of various CALD patients (rather than enrolling any patients into an active study, such as usually occurs in a clinical trial). The researchers used 174 MRIs from 36 pre-symptomatic patients, some of whom have progressive CALD, and some of whom have the arrested form of the disease. Starting with the earliest scans, the researchers used specialist image analysis software to calculate the size of the cerebral lesions in each image. A lesion is an area of tissue that has been damaged through injury or disease, and occur in CALD as a result of the cell damage caused by ABCD1 mutation. This damaged tissue reacts differently with the magnetic field used to conduct an MRI scan, and it will therefore appear contrasted against the healthier brain tissue surrounding the lesion. Once they had a value for volume of the lesion, the researchers were then able to assess how this measurement changed over time by plotting lesion volume against the age at which the patient had had the scan on a graph. It was found that there was an inverse correlation between patient age and a couple of parameters of lesion growth; meaning the younger the patient, the faster the lesion was developing.

Overall, the researchers found that there is utility in measuring and assessing how newly developing cerebral lesions change over time using their technique. Indeed, it was found that the trajectories of lesion growth differ between the progressive and arrested subtypes of CALD before symptom onset. For example, those patients in whom newly developed lesions grew rapidly were those with progressive CALD. Cerebral lesions in patients known to have arrested CALD were found to not have grown at the same rate as those with the progressive subtype. Importantly, the researchers also noted that their way of measuring how cerebral lesions were developing was more sensitive than the standard method for measuring the extent of neurological damage in CALD. For example, they found significant differences in the size of a given lesion correlated to the severity of symptoms experienced by an individual which both had an ‘LS score’ (the standard method of scoring) of 1. This study is especially important in light of the recent addition of adrenoleukodystrophy to the Recommended Uniform Screening Programme. It should now be possible to monitor for new cerebral lesions from birth and accurately predict which patients are eligible for therapy.

ALSP

Vigil Neuroscience begin work to better understand ALSP in order to identify parameters which can be used to inform design of a clinical trial for a potential treatment.

From the article –  Vigil Neuroscience Announces First Subject Enrolled in a Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) – access: https://www.businesswire.com/news/home/20210915005126/en/Vigil-Neuroscience-Announces-First-Subject-Enrolled-in-a-Natural-History-Study-of-Patients-with-Adult-Onset-Leukoencephalopathy-with-Axonal-Spheroids-and-Pigmented-Glia-ALSP

Adult-onset leukoencephalopathy with axonal spheroids and pigments (ALSP) is a rare neurodegenerative condition caused by mutation in the gene CSF1R. The mutation leads of dysfunction of a type of cell in the central nervous system (i.e., the brain and spinal cord), known as microglia. This microglial dysfunction leads to damage to the nerve cells of the CNS, resulting in neurological symptoms in patients affected by ALSP. Currently, there are no approved treatments for ALSP, and more generally, a large unmet need for treatment for other neurological diseases thought to be characterised by microglial dysfunction, including Alzheimer’s Disease. Vigil Neuroscience is a pharmaceutical company focussed on developing therapeutics specifically targeting this cell type. The compound VGL101, currently undergoing development with the view of shortly obtaining ‘Investigational New Drug’ (IND) status from the FDA, is one such therapeutic. The scientific rationale behind VGL101 is that the cellular pathways in microglia which become disrupted following mutation of CSFR1 may also be activated by a protein known as TREM2. VGL101 stimulates TREM2, thus compensating for CSFR1 loss. Obtaining IND status will mean that Vigil Neuroscience will be able to begin conducting clinical trials with the aim of establishing whether VGL101 could be a viable treatment option for ALSP.

Prior to any clinical trials beginning with VGL101 in this patient group however, Vigil Neuroscience have launched a prospective ‘natural history’ study of ALSP, which was designed in collaboration with patients, physicians and other advocates. Researchers running the study will follow a number of individuals with ALSP across the US, Canada and Europe. The aim of this study is to better understand how ALSP progresses, with the view of identifying relevant clinical measures which can later be used to assess the impact of VGL101 treatment. Researchers will evaluate the results of imaging and other clinical tests ALSP patients undergo, with the view of determining, for example, which biomarkers (a measurable indicator of a state of health or disease in a person) will be most useful to incorporate into a future VGL101 clinical trial.

 

Links to Leukodystrophy research and trials

ALD

Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy
https://pubmed.ncbi.nlm.nih.gov/34499753/

Translational and clinical pharmacology considerations in drug repurposing for X-linked adrenoleukodystrophy—A rare peroxisomal disorder
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15090?af=R

X-linked adrenoleukodystrophy presenting as progressive ataxia and pure cerebellar involvement
https://www.scielo.br/j/anp/a/c6xygq7vcBSyKRCtg5Kw85N/?lang=en

 

CADASIL

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation
https://pubmed.ncbi.nlm.nih.gov/34558736/

 

Cockayne Syndrome

Riaan Research Initiative funds Cockayne syndrome gene replacement therapy research at UMass Chan Medical School
https://www.umassmed.edu/news/news-archives/2021/10/riaan-research-initiative-funds-cockayne-syndrome-gene-replacement-therapy-research-at-umass-chan-medical-school/

 

Giant Axonal Neuropathy (GAN)

Clinical-Stage AAV9 Gene Therapy Program, TSHA-120, for the Treatment of Giant Axonal Neuropathy, a Rare and Severe Neurodegenerative Disease
https://www.businesswire.com/news/home/20210412005343/en/Taysha-Gene-Therapies-Acquires-Exclusive-Worldwide-Rights-to-Clinical-Stage-AAV9-Gene-Therapy-Program-Now-Known-as-TSHA-120-for-the-Treatment-of-Giant-Axonal-Neuropathy-a-Rare-and-Severe-Neurodegenerative-Disease#:~:text=TSHA-120%20is%20an%20intrathecally%20dosed%20AAV9%20gene%20therapy,focused%20on%20finding%20treatments%20and%20cures%20for%20GAN.

 

GM1 Gangliosidosis

Sio Gene Therapies Announces Dosing of First GM1 Gangliosidosis Early Infantile (Type I) Patient in Ongoing Phase 1/2 Study of AXO-AAV-GM1 Gene Therapy
https://investors.siogtx.com/news-releases/news-release-details/sio-gene-therapies-announces-dosing-first-gm1-gangliosidosis

 

GM2 Gangliosidosis

Taysha Gene Therapies Receives Orphan Drug Designation from the European Commission for TSHA-101 for the Treatment of Infantile GM2 Gangliosidosis
https://www.businesswire.com/news/home/20210929005286/en/Taysha-Gene-Therapies-Receives-Orphan-Drug-Designation-from-the-European-Commission-for-TSHA-101-for-the-Treatment-of-Infantile-GM2-Gangliosidosis

 

IntraBio Reports Further Detail On Positive Data From IB1001 Multinational Clinical Trial For The Treatment of GM2 Gangliosidosis
https://finance.yahoo.com/news/intrabio-reports-further-detail-positive-131500732.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAAEt0vbRchoE1czGLyg9AzTvwGcO81EjFSDn3_7tOP7kVyrXEllNMarBwUY-NdYKxQDuabPxo1Rd_TSwhoL-XVV6vqXXohF6YoMPq_tspNokDdGBaaq4jZqPzNNQ4RDV4C__PWNU2p068FhBS2IDlJaPcwnqyFW6Re1G7IfyypQ1j

 

Krabbe Disease

Polaryx Therapeutics Receives FDA Orphan Drug Designation for PLX-200 for Treatment of Krabbe Disease
https://www.pharmtech.com/view/polaryx-therapeutics-receives-fda-orphan-drug-designation-for-plx-200-for-treatment-of-krabbe-disease

 

MLD

Lead Gene Therapy Programs to Advance the Treatment of Neurologic and Neuro-oncologic Diseases to include metachromatic leukodystrophy (MLD)
https://www.biospace.com/article/releases/affinia-therapeutics-announces-indications-for-lead-gene-therapy-programs-to-advance-the-treatment-of-neurologic-and-neuro-oncologic-diseases-supported-by-multi-year-manufacturing-agreement-with-lonza-group/