Research Summary Aug 2021

Alex - The Leukodystrophy Charity

Adult Polyglucosan Body Disease (APBD) & GM2 gangliosidosis

Preclinical programs demonstrate potential gene therapies for the treatment of APBD and GM2


Taysha Gene Therapies has announced promising new data for multiple gene therapy programs. These have included gene therapies for APBD and GM2 gangliosidosis:


TSHA-112 for Adult Polyglucosan Body Disease (APBD)

APBD is caused by mutations in the GBE1 gene. The GBE1 creates a glycogen branching enzyme which is involved in producing a sugar called glycogen, a source of stored energy. When mutations occur the enzyme creates abnormal glycogen molecules called Polyglucosan bodies. These accumulate and cause damage, particularly to nerve cells, although the reasons for this are not fully understood. TSHA-112 induced significant reductions in GYS1 mRNA, GYS1 protein, abnormal glycogen accumulation, and polyglucosan bodies throughout the brain in an APBD knockout mouse model. TSHA-112 decreased neuroinflammatory (inflammatory response within the brain) markers across three distinct mouse models.


TSHA-119 for GM2 gangliosidosis

GM2 is caused by mutations in the HEXA gene which reduces its ability to produce an enzyme called beta-hexosaminidase A. This enzyme breaks down GM2 ganglioside. When this is not broken down, it builds up in nerve cells of the brain and spinal cord, causing the described symptoms. TSHA-119 caused a significant, dose-dependent reduction of GM2 accumulation at 20 weeks in mice that were dosed intrathecally (administered into the spinal theca, in the spinal cord) at postnatal day 1 or at 6 weeks of age.


There are no approved disease modifying therapies for either of these conditions in Taysha Gene Therapies portfolio. Both gene therapies are being advanced into IND/CTA (filing with a Regulatory Authority that must be made prior to commencing clinical testing in humans) enabling studies.

Alex - The Leukodystrophy Charity

Adrenoleukodystrophy (ALD)

Gene rescue potential therapeutic strategy for ALD treatment


Adrenoleukodystrophy (ALD) is caused by various pathogenic mutations in the X-linked ABCD1 gene, which lead to metabolically abnormal accumulations of very long-chain fatty acids in many organs. This study explores a possible treatment of ALD in ALD model mice. They performed in vivo HITI-mediated gene editing, using AAV9 vectors, delivered via intravenous (into a vein) administration. The results showed that sensitive diagnostic markers for ALD were significantly reduced, suggesting that HITI-mediated mutant gene rescue could be a promising therapeutic strategy for human ALD treatment.


Drug for the effective treatment of X-ALD


Minoryx Therapeutics has released findings which supports the use of Leriglitazone in treating X-ALD and other neurodegenerative conditions. The results obtained suggest that leriglitazone has an improved profile for treating X-ALD, compared with other drugs, including pioglitazone. Although previously found to be effective with AMN, this new evidence suggests Leriglitazone could be beneficial for all X-ALD clinical manifestations, including Cerebral ALD.

Alex - The Leukodystrophy Charity

Adrenomyeloneuropathy (AMN)

Preclinical evidence of drug to treat AMN in mice models


Autobahn Therapeutics has preclinical data of ABX-002 to be used for the treatment of Adrenomyeloneuropathy (AMN). AMN is characterized by a toxic build-up of Very Long Chain Fatty Acids (VLCFAs) in the Central Nervous System (CNS) and periphery, accompanied by demyelination (loss or destruction of myelin). This build-up is driven by mutations in the ABCD1 gene which encodes a transporter that takes VLCFAs into peroxisomes for degradation.


ABX-002 focused on addressing the toxic build-up of VLCFAs in AMN patients. ABX-002 acts by increasing expression of ABCD2, a compensatory transporter which functionally compliments defective ABCD1 and is a direct target gene of thyroid hormone. By increasing thyroid hormone signaling, ABCD2 expression is increased, leading to a reduction of VLCFAs.


The data shows that the administration of ABX-002 resulted in beneficial responses in mice models and supports the advancement toward clinical evaluation for the treatment of people with AMN.

Alex - The Leukodystrophy Charity

Alexander Disease

Clinical study of medicine to treat Alexander Disease


Alexander disease is caused by a genetic mutation that leads to overproduction and toxic accumulation of glial fibrillary acidic protein (GFAP) in the brain. Ionis have initiated a clinical study of ION373, an investigational antisense medicine designed to reduce the level of GFAP.


The multi-centre study includes up to 58 patients with Alexander disease. Patients will receive ION373 or placebo (treatment with no therapeutic value) for a 60-week period, after which all patients in the study will receive ION373 for a 60-week treatment period. ION373 is one of Ionis’ wholly owned rare disease medicines which the company hopes to commercialise if proven safe and effective.

Alex - The Leukodystrophy Charity

Canavan Disease

Natural History of Canavan Disease; new cases and comparison with patients from literature


Canavan disease (CD) is a genetic degenerative brain disorder caused by deficiency of the enzyme aspartoacylase (ASPA). The loss of ASPA activity results in an accumulation of Nacetylaspartic acid (NAA) in the brain and other parts of the body. NAA is suspected to function as a molecular water pump, leading to fatal brain disease for which there is currently no effective treatment.


The study looked at the clinical course of Canavan Disease in 23 patients in comparison with previous cases. They key findings: –

  • Onset of symptoms: 0-6 months
  • Psychomotor Development: limited to abilities gained in first year if life
  • Macrocephaly (over large head): apparent between 4-18 months of age
  • Seizure frequency: highest towards 10 years old
  • Population: occurs more frequently outside Ashlenazi Jewish communities than previously reported


The early identifying clinical symptoms of Canavan Disease are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. A Canavan Disease severity score with assessment of 11 symptoms and abilities was developed. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.


Clinical trial to validate new gene therapy for treatment of Canavan Disease


The purpose of this study is to validate a new technology targeted to the cells most affected by Canavan Disease in the safest way possible. Canavan Disease is a congenital white matter disorder caused by mutations to the gene encoding for aspartoacylase (ASPA) which expression is restricted to the oligodendrocytes. This protocol directly targets oligodendrocytes in the brain, which are intimately involved with disease initiation and progression. Targeting oligodendrocytes offers the safest and most direct therapy for affected individuals.


The latest generation AAV viral vector (rAAV-Olig001-ASPA) involves direct administration of gene therapy to affected regions of the brain. Patients with a diagnosis of typical Canavan Disease who meet all eligibility criteria may be enrolled.

Alex - The Leukodystrophy Charity

Giant Axonal Neuropathy (GAN)

Clinical Stage Gene Therapy Program for the treatment of GAN


Taysha Gene Therapies has acquired rights to a gene therapy program, TSHA-120, for the treatment of GAN.  GAN is a rare inherited genetic disorder that affects both the central and peripheral nervous systems and is caused by loss-of-function mutations in the gene coding for gigaxonin.


The preclinical studies showed efficacy of TSHA-120 when tested with rodent models with GAN. The results demonstrated a dose-response relationship with arrest of disease progression at the second highest dose level, at one year post treatment. Long-term results demonstrated that treatment with TSHA-120 at multiple dose levels was well-tolerated with no severe drug-related adverse events.


The primary endpoint is safety, with secondary endpoints measuring efficiency of the gene therapy with clinical markers. Before the end of the year, Taysha intends to request an End-of-Phase meeting with the FDA, European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan to discuss the regulatory pathway for TSHA-120.

Alex - The Leukodystrophy Charity

Glutaric Aciduria Type 1 (GA1)

Impact of Newborn screening programs for Glutaric Aciduria Type 1


Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome.


A meta-analysis, examination of data from a number of independent studies of the same subject to determine overall trends, was performed on studies of GA1 where at least one individual in the study was identified by NBS. The results showed that NBS programs for GA1 have an overall positive effect on the neurological outcome of affected individuals but their success critically depends on the quality of therapy.

Alex - The Leukodystrophy Charity

GM1 gangliosidosis

GM1 gangliosidosis Clinical Gene Therapy Trial


Sio Gene Therapies is running a clinical trial of AXO-AAV-GM1, AAV9-based gene therapy, for the treatment of GM1 gangliosidosis. GM1 gangliosidosis is a progressive and fatal paediatric lysosomal storage disorder caused by mutations in the GLB1 gene that cause impaired production of the β-galactosidase enzyme. Currently, there are no FDA-approved treatment options for GM1 gangliosidosis.


The previous data from the study demonstrated that AXO-AAV-GM1 was well-tolerated with a favourable safety profile with no serious adverse events attributed to the gene therapy and provided early indications of clinical disease stability.  The new biomarker data from cerebrospinal fluid (CSF) collected at 6 months, showed that there was a reduction from baseline in GM1 ganglioside in 4 out of 5 children receiving low-dose cohort. However, the one child who disease was most advanced at baseline showed an increase in CSF GM1 Ganglioside. There will be another data read out at 12 months, later this year, to provide further evidence regarding the durability of the AAV9 gene therapy and its potential to slow or halt the progress of GM gangliosidosis.

Alex - The Leukodystrophy Charity

Late Onset Leukodystrophies

Spastic paraplegia and screening for late-onset Leukodystrophies


A study to investigate the frequency of late-onset leukodystrophies when patients present with spastic paraplegia (weakness and spasticity (stiffness) in the leg muscles). There have been previous reports which have shown that late-onset leukodystrophies, including Adrenoleukodystrophy and Krabbe disease, may present as spastic paraplegia with the absence of the characteristic white matter lesions on neuroimaging. This could result in individuals being misdiagnosed as having hereditary spastic paraplegia (HSP).


In the study 112 patients with spastic paraplegia were tested for leukodystrophes. 13 were found to have a leukodystrophy despite there being no evidence of leukodystrophy on their neuroimaging. The study recommends patients with late-onset spastic paraplegia should be screened for leukodystrophies, irrespective of the presence of additional complicating symptoms and neuroimaging abnormalities.

Alex - The Leukodystrophy Charity

Metachromatic Leukodystrophy (MLD)

Preliminary signs of the efficacy of gene therapy for MLD


Passage Bio have been evaluating the pre-clinical efficacy of the adeno-associated virus (AAV)-mediated gene therapy for MLD. A mouse model was developed and utilised in reproducing key aspects of human metachromatic leukodystrophy (MLD) neuropathology to enable evaluation of efficacy of AAV gene therapy. This model reproduces important aspects of human leukodystrophy neuropathology, including key biomarkers. Preliminary findings showed the administration of Passage Bio’s gene therapy significantly reduced the neurological deficits of MLD in this model.


Gene Therapy for MLD rejected by NICE


Orchard Therapeutics’ Libmeldy (OTL-200), a gene therapy for MLD, has been rejected for NHS use by NICE in draft guidance. There is evidence of the short-term benefit of Libmeldy but assumptions about its long-term effects are uncertain, making it unclear whether it will offer value for money to the NHS.


MLD is an inherited neurodegenerative disorder caused by a deficiency in the ARSA gene coding for the enzyme arylsulfatase-A, which allows sulphatide compounds to build up in the body. At high levels, sulphatides become toxic to nerve cells, destroying the insulating myelin sheath that surrounds them and preventing them from working properly. Libmeldy is an ex vivo, autologous, hematopoietic stem cell-based gene therapy – meaning it is based on cells derived from a patient’s own body – and is designed to replace the defective ARSA gene with a working copy. It was approved by the European Commission last December, becoming the first therapy to be registered for early-onset MLD, on the strength of clinical data showing that it could slow down the loss of motor and cognitive function in children with the disease.


The decision kicks off a comment period and further negotiations between the company, NICE and NHS England on the price of Libmeldy which Orchard has already offered a confidential discount on the therapy. The appraisal committee is scheduled to look at Libmeldy again on 6 October.

Alex - The Leukodystrophy Charity

Myelin rejuvenation

Researchers identify a molecule critical to functional brain rejuvenation


A new study has identified a molecule called ten-eleven-translocation 1 (TET1) to be a required component of myelin repair. Glial cells are highly responsive to external signals and injuries, they can detect changes in the nervous system and form new myelin, which wraps around nerves and provides metabolic support and accurate transmission of electrical signals. TET1 modifies the DNA in specific glial cells in adult brains so they can form new myelin in response to injury.


The study found TET1 in young adult mice were essential to promote a healthy dialogue among cells in the central nervous system and for guaranteeing proper function. In older mice the TET1 progressively declined, so that the DNA could no longer be properly modified to guarantee the formation of functional myelin. Impaired myelin formation has been reported in individuals with neurodegenerative diseases as one of the causes of their progressive clinical deterioration. It is hoped this study and future work could have implications for the recovery of cognitive and motor functions in older people and patients with neurodegenerative diseases.

Alex - The Leukodystrophy Charity

Rare Diseases

Project hoping to shorten diagnostic odysseys for Rare Diseases


An initiative called the Tretabolome project has been launched by Solve-RD. Solve-RD is a research project funded by the European Commission for five years (2018-2022) to solve large numbers of rare diseases and improve diagnostics of rare disease patients. The Tretabolome project is an ‘online platform to collect and provide treatment information geared to specific genes and gene variants (mutations) to any and all healthcare professionals, not just the specialists brought in as the light at the end of the diagnostic tunnel comes into view’.


The Tretabolome project aims to reduce the time between genetic diagnosis and start of treatment. There has been an improvement in the availability of genetic diagnosis and growing rare disease treatments, with a development in gene therapies and increase in number of orphan drug applications. The targeted treatments for rare disease patients are only availability to a minority but it is hoped that with recent treatment developments this will increase in time. The project plans to include more diseases in the future which could be of benefit of those with other rare diseases.

Alex - The Leukodystrophy Charity

Vanishing White Matter

Clinical trial for treatment of Vanishing White Matter


The Center for Childhood White Matter Disorders (CCWMD) are planning to conduct a clinical trial in children with VWM. The trial will be investigating the use of drug called Guanabenz, which is a well-know medicine for the treatment of high bloody pressure. It will evaluate whether the drug is effective in slowing, stabilising or improve the brain white matter abnormalities in VWM.


It has been shown that long term high dose Guananbenz treatment improves motor function and improvement of brain pathology, in laboratory mice with VWM. The effect of Guananbenz in humans is yet to be investigated in the treatment of VWM. They have released an eligibility criteria for participation in the trial, if met, the child will be evaluated to determine whether they can participate in the trial. They require clinical information, results of the genetic test confirming VWM and the MRIs of the child to start the process of participating in the trial.

Alex - The Leukodystrophy Charity