Research Summary July 2021

Alex - The Leukodystrophy Charity

Evidence supporting Eli-cel as a potential gene therapeutic treatment for adolescent cerebral adrenoleukodystrophy.—EU-Press-Release_eli-cel-EBMT-2021_FINAL.pdf?rev=873f1c6648ca4232891a4ec3749fdabe&hash=E470507B881D4FB9DE9576F11A92F4F3 (accessed 13/06/2021) (accessed 13/06/2021)


The gene therapy company bluebird bio recently announced results from a number of studies which are aiming to investigate the potential of the therapeutic Eli-cel as a treatment for cerebral adenoleukodystrophy (C-ALD).

(C-ALD) is caused by mutations in a gene known as ‘ABCD1’. The result of this mutation is that a type of biological molecule (very long chain fatty acids, or VLCFA) is no longer properly degraded and accumulates to toxic levels. In the central nervous system (i.e., cells of the brain and spinal cord), high VLCFA levels are very damaging, hence why C-ALD primarily manifests in neurological symptoms. Eli-cel is a one-time gene therapy which is designed to introduce a non-mutated version of ABCD1 into a patient. To do this, blood stem cells are taken from the bone marrow of a person affected by C-ALD, and a ‘corrected’ version of ABCD1 is introduced into these blood stem cells by way of a non-harmful virus. The stem cells containing the correctly functioning version of ABCD1 are then re-introduced into the patient, where the hope is that these cells with divide and proliferate throughout a patient’s body, thus preventing the toxic build up of VLCFA. This treatment differs from other bone marrow transplant treatment from C-ALD in that with Eli-cel, the patient’s own stem cells are used (i.e., the treatment is autogenic). There are serious immune complications associated with using another person’s cells to perform a bone marrow transplant (i.e., an allogenic transplant), for example, the risk of graft versus host disease.

Firstly, bluebird bio report an update from the phase 2/3 clinical trial, the ‘Starbeam’ study (technically known as ALD-102). 24 months following treatment, 90% of patients (27/30) who had received Eli-cel were both alive and free of any major functional disabilities (MFDs). 2 boys who have received Eli-cel but have not yet reached 24 months post treatment also show no sign of MFD. Within this group, 14 boys who have reached at least the 5-year follow up point continue to be living free of any MFDs. Of these boys, some have reached almost seven years of follow-up. Almost all patients also have a stable neurological score, with 23 patients maintaining a neurological function score of 0, indicating absolutely no impairment of neurological function. Altogether, the results from the ALD-102 trial suggest that treatment with Eli-cel may durably stabilise disease, prevent disease progression and consequently preserve as much neurological function as possible in boys affected by C-ALD. Of the total 32 patients who have received Eli-cel in ALD-102, 27 have completed the study and are now enrolled in a long-term follow-up study (LTF-304)

Bluebird bio have also recently announced data from the Phase 3 trial ALD-104. This trial aims to assess the how well Eli-cel works in C-ALD patients who have undergone ‘myeloablation’ using busulfan and fludarabine, chemotherapeutic drugs which are different to those which had been used in the original ‘Starbeam’ ALD-102 study (busulfan and cyclophosphamide). Myeloablation refers to the process whereby patient bone marrow activity is suppressed using these chemotherapeutic drugs, preventing the formation of new white blood cells in the patient. This step is required to ensure that when the blood cells containing the corrected ABCD1 gene are re-introduced, they will not be ‘outcompeted’ or replaced by the patient’s original cells containing the mutated version of ABCD1, so that maximum therapeutic effect can be obtained. This trial has only been running approximately 9 months, so no data is available regarding the neurological score and presence of MFD in these patients. However, the treatment is reported as safe. Due to the nature of this treatment, there are reports of complications, although none over and above what would be expected to be associated with treatment of these drugs. There have been no reports of failure or rejection of the transplant and no incidences of graft versus host disease.

Alex - The Leukodystrophy Charity

Using induction of stearyl-CoA-desaturase expression to alleviate accumulation of very long-chain fatty acids in laboratory models of X-ALD (accessed 13/06/2021)

X-linked adrenoleukodystrophy is caused by mutations in the gene ABCD1. This gene contains the instructions for making a cellular protein known as ‘very long chain fatty acid transporter’ (VLCFA), which helps to metabolise ‘very long chain fatty acids’ (a type of biological molecule) in the cell. When VLCFA does not function correctly, such as in X-ALD patients who have ABCD1 mutations, these fatty acids build up to toxic levels and cause damage to the nervous system.

In this study, researchers from the University of Amsterdam describe how they have found a chemical which may be able to alleviate some of the cellular ‘stress’ and toxicity caused by very long-chain fatty acid build-up. This chemical is called chloroquinine and induces the expression of another gene which in a certain fashion appears to compensate for VLCFA dysfunction. This second gene carries the instructions for making another cellular protein, stearyl-CoA-desaturase(SCD), which can convert the very long chain fatty acids into a less toxic form, therefore causing less damage to cells.

The researchers then used another method to induce SCD expression in mice which have been engineered to carry a mutation in the mouse equivalent of ABCD1, who therefore experience some of the symptoms associated with X-ALD in humans. As expected, they found that the treated mice experience a decreased in very long-chain fatty acids in tissues which are normally highly affected in X-ALD. However, in contrast to their results in cells, VLCFAs were not reduced to a ‘normal’ level in the mice, and the treated mice did experience liver toxicity. This study did not assess whether inducing expression of SCD in mice reduced nerve cell degeneration, which would be a much better indicator of whether this strategy is a viable therapeutic approach in human X-ALD patients. It may be that this result would have been found if the mice were treated with the SCD inducing agent for a much longer period of time. However, this was not possible due to the liver toxicity associated with treatment with this agent. Altogether, although the results found in this study are promising, there are notable limitations associated with a therapeutic strategy aiming to induce SCD expression – not only liver toxicity, but also the risk of cardiac complications and damage to the retina. Much more work needed in this area before a clinical trial could be possibly conceived, but the work opens an interesting avenue of research alternative to gene therapy.

Alex - The Leukodystrophy Charity

Neurofilament light-chain as a potential biomarker for measuring neurodegeneration in X-linked adrenoleukodystrophy. (accessed 13/06/2021)

X-linked adenoleukodystrophy, caused by mutations in the gene ABCD1, is a variable disease, and may manifest either as adrenomyeloneuropathy (AMN) or cerebral adenoleukodystrophy (C-ALD).

In this study, researchers investigated whether the cellular protein ‘neurofilament light-chain’ (NfL) could be used as a biomarker of neurodegeneration in these conditions. In medicine, a biomarker is any kind of biological sign which can be measured to give an indication of health or disease in a person or animal. For example, insulin may be used as a biomarker of diabetes, and auto-antibodies are a biomarker associated with various autoimmune diseases.

When the researchers examined levels of NfL in patients affected by AMN, they found that higher levels of NfL were correlated with higher grade myelopathy-related disability; that is, disability caused by damage or dysfunction of the spinal cord. The researchers also found that NfL levels could be used to predict whether a person affected by AMN would then later go onto develop C-ALD. In C-ALD, patients, it was found that NfL levels were correlated with the severity of brain lesions. In some rare cases, it was found that unusually low NfL levels could be associated with previously unrecognized slowly progressing version of C-ALD. When progressive damage to cells of the central nervous system was stopped, i.e., when a patient underwent a bone-marrow (or stem cell) transplant, it was found that NfL levels gradually normalised. Altogether, the results reported by the researchers in this study show that NfL levels can be indicative of inflammation and disease progression in C-ALD patients. Therefore, moving forward, there is perhaps potential for measurement of NfL levels to be used to inform clinical decisions, or to be used as a read-out of whether or not a therapeutic is working as intended in a clinical trial.

Alex - The Leukodystrophy Charity

The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis (accessed 13/06/2021)

Alpha-mannosidosis is a rare inherited disorder caused by mutations in the gene MAN2B1. This gene contains instructions for making the cellular protein alpha-D-mannosidase. Alpha-D-mannosidase is an enzyme, and functions to break down other cellular proteins. In its absence, these cellular proteins build up to toxic levels and cause damage to numerous organs and systems of the body. People affected by alpha-mannosidosis may experience intellectual disability, hearing loss, skeletal abnormalities or dysfunction of the immune system.

SPARKLE is a new registry of alpha-mannosidosis patients established with the aim of understanding the long-term safety and effectiveness of using ‘velmanase alfa’ to treat non-neurological symptoms in alpha-mannosidosis patients with mild to moderate disease. Velmanase alfa (otherwise known by its commercial name Lamzede) is a type of enzyme replacement therapy (therefore compensating for loss of function of alpha-D-mannosidase), and the SPARKLE registry is a post-approval commitment for the European marketing authorisation for this drug.

Patient enrolment into the SPARKLE registry started in 2020, and patients will be followed for up to 15 years. Any patient with a diagnosis of alpha-mannosidois from the European Union who is willing to participate, regardless of whether or not they are being treated with velmanase alfa, will be eligible for entry onto the registry. Criteria such as, for example, whether any adverse reactions to velmanase alfa occur, will be measured, as well as the results of physical examinations and electrocardiograms. Overall, data collected from people enrolled onto the registry will aid not only with the understanding of how well velmanase alfa is working as a standard treatment for alpha-mannosidosis patients, but also with how this extremely rare disease may manifest and progress in different ways in different people.

Alex - The Leukodystrophy Charity

Forge Biologics Receives FDA Fast Track, Orphan Drug and Rare Paediatric Disease Designations (accessed 13/06/2021)

Forge Biologics, a company specialising in the manufacture and testing of gene therapeutic products, have recently announced that the US Food and Drug Administration has granted Fast Track, Orphan Drug Designations and Rare Paediatric Disease designations to FBX-101, a treatment it has developed for Krabbe Disease. Krabbe Disease is a type of leukodystrophy caused by mutations in the gene GALC, which contains instructions for making a protein responsible for breaking down a variety of other biological molecules in the cell. When these other molecules accumulate, they cause damage to cells of the central nervous system (i.e., the brain and spinal cord), causing neurological symptoms in affected people. The FDA Fast Track designation is designed to facilitate the development and expedite the review of drugs to treat serious, life-threatening conditions and fulfil an unmet medical need (for example, where the drug is providing a therapy where none currently exists, such as is the case in Krabbe Disease). The designation may confer eligibility for accelerated approval and priority review, rolling review (which would also expedite the process of allowing patient access to the drug) as well as allowing for more frequent contact with the FDA in regard to the drug development plan. The FDA Orphan Drug Designation was introduced to encourage the development of drugs to treat conditions affecting fewer the 200,000 people in the US and confers a number of benefits to the pharmaceutical company in question, as well as potentially allowing for priority review. The Rare Paediatric Disease designation confers similar benefits, but is concerned with the development of drugs for diseases affecting a small number of children under the age of 18.

Forge Biologics is actively recruiting patients for enrolment in a phase 1/2 clinical trial of FBX-101, the first intravenous gene therapeutic for patients with Krabbe disease. The aim of FBX-101 is to introduce a ‘corrected’ copy GALC into patients using a type of non-harmful virus. The pre-clinical (i.e., laboratory) studies carried out on FBX-101 have shown promise; increasing the survival and decreasing improving physiological symptoms in mice which have been designed to experience a disease course similar to that seen in human Krabbe Disease patients. Altogether, the commencement of the trial and the designations awarded by the FDA are important steps towards finally obtaining an FDA-approved treatment for Krabbe Disease.

Alex - The Leukodystrophy Charity

Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a rare type of leukodystrophy caused by mutations in the gene PLP1, which contains the instructions for making a cellular protein known as ‘proteolipid protein’. Mutations in PLP1 can occur in a variety of places in the gene, some are linked to the development of severe and fatal form of PMD, and some are linked to a milder form of the disease. Those mutations linked to more serious forms of the disease include ‘substitutions’ (the swapping of a single subunit of DNA for another, erroneous subunit, and ‘copy variations’ (a multiplication of the number of PLP1 copies in a cell). Unusually, researchers have found that when PLP1 is completely absent, PMD manifests in a much milder form, suggesting that attempting to completely suppress PLP1 function may be a viable therapeutic strategy for PMD patients. The scientists involved in this study demonstrated that when the PLP1 gene was completely and permanently deleted in a mouse ‘model’ of human PMD, both nerve function and lifespan were increased. This type of strategy would, at least currently, not be possible to carry out in humans due to the nature of the genetic engineering involved. However, the researchers found that they could administer a type of chemical which decreases PLP1 expression in mice in a way which is currently feasible to carry out in humans. In these mice, increased nerve function was observed, as well as improved motor and respiratory function and lifespan. Demonstration that this treatment works, at least in mice, is a promising development not only in the field of PMD research, but also other diseases characterised by nerve cell dysfunction. The authors of this study make clear that further preclinical (laboratory) work will be needed to optimise this potential treatment, but results from work so far has been very promising, as only a single dose of the chemical in question can elicit a significant and sustained improvement in the symptoms being experienced by the PMD mice.

Alex - The Leukodystrophy Charity