Bone Marrow Metachromatic Leukodystrophy

Treatment

Currently, no effective treatment is available to reverse the deterioration and loss of function that Metachromatic Leukodystrophy (MLD) causes. In individuals with asymptomatic late-infantile and early-juvenile forms of the disease, bone marrow or cord blood transplantation may stabilize neurocognitive function; however, symptoms of motor function loss frequently progress. Mildly symptomatic and asymptomatic late-juvenile and adult-onset forms are more likely to be stabilised with bone marrow transplantation because of the slower progression of the disease.

In addition to bone marrow transplantation, gene therapy is under development as a possible solution to correct the underlying genetic abnormality. Gene therapy using the patient’s own cells has the advantage of not having the risks of graft-Vs-host disease in Bone Marrow Transplantation, and always having a source. Researchers are developing innovative methods to overcome the barrier of getting adequate enzyme activity into the CNS (central nervous system). One such procedure involves transduction of neurospheres with a vector containing arylsulfatase A. Gene therapy has had success in treating X-linked severe combined immune deficiency (SCID), adenosine deaminase deficiency-SCID, and chronic granulomatous disease. A phase I/II clinical trial is actively recruiting to evaluate gene therapy for metachromatic leukodystrophy. Further information can be obtained regarding this clinical trial at the ClinicalTrials.gov Web site under its identifier: NCT01560182.

A therapeutic strategy useful in other metabolic storage diseases is direct enzyme replacement. The difficulty with this strategy has always been getting adequate enzyme activity into the CNS. Intravenous injections of a recombinant human Arylsulfatase-A in a mouse model of metachromatic leukodystrophy initially demonstrated no evidence of impact on CNS stores of sulfatide. However, with a significant increase in the injection frequency, researchers were able to demonstrate a reduction in CNS stores.

In the United States and Europe, clinical trials are evaluating the safety and efficacy of a recombinant human arylsulfatase A (rhARSA) enzyme, metazym. The new drug had obtained Orphan Drug status from the US Food and Drug Administration (FDA) in early 2008. In the United States, the sponsor for rhARSA is Shire Human Genetic Therapies in Cambridge, Massachusetts. The phase I clinical trial for its use in children with late-infantile metachromatic leukodystrophy showed that the drug was safe. Unfortunately, the extension study was terminated due to a lack of efficacy (ClinicalTrials.gov, identifier NCT00681811). With the thought that the route of administration may allow for better drug concentrations in the CNS, a multicenter phase I/II clinical trial has been developed to evaluate the safety and efficacy of rhARSA administered intrathecally (ClinicalTrials.gov, identifier NCT01510028).This study is currently open to accrual.

Another therapeutic approach under study in mice is the use of oligodendroglial cell therapy. Givogri et al reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain.These cells engrafted and integrated without disruption or tumor formation. Compared with untreated control mice, the treated mice had reduced sulfatide accumulation in the CNS with increased enzyme activity and prevention of motor deficits. This therapeutic approach is not available for humans at this time.

 

Bone marrow transplantation

Careful evaluation and counseling of patients/parents prior to bone marrow transplantation is absolutely essential. It can take between 6 months to one year for enough cells to be produced and to migrate to affected areas to halt progression and, during this time, the patient’s condition continues to deteriorate. Although transplantation may be successful, enzyme release to surrounding tissues is unpredictable and the results vary widely. Many children who have a BMT continue to deteriorate, albeit more slowly. It is Adult-Onset MLD which seems to be halted by BMT and there are now cases of sufferers who have been stable for between 20—25 years who are still walking, talking, eating normally and leading an active and happy life. However, the downside is that they still have some form of dementia-like symptoms and can rarely live without some form of care.

In addition, the transplantation conditioning regime and the period just after transplant when the body is fighting to produce new cells, means that there is often a brief period of accelerated deterioration. This is why it is important that the recipient has none or very few symptoms at the time of BMT.

BMT carries significant morbidity and mortality rates, which means that risks versus potential stabilisation need to be carefully stated by the medical staff and understood and considered by the patient/parent.

Medical evaluation for transplantation includes careful neuropsychological and developmental testing to establish current levels of function for comparison with future results. There will need to be an assessment of the organ systems, including cardiac, pulmonary, liver, and kidney functions as well as dental checks to ensure no existing infection could cause problems when the patient is immunosuppressed. There will also need to be a recent brain MRI and a thorough neurologic examination.

An appropriately matched and unaffected relative, generally a sibling, whose cells produce an adequate level of Arylsulfatase A, should be used as a donor. An appropriately matched unrelated donor can be used, although this transplantation process carries higher morbidity and mortality rates and, particularly, a greater risk of Graft-vs- Host disease. Bone marrow or placental (cord) blood can be used as a source of stem cells but cord blood may not produce enough cells for a fully grown male recipient.

The biggest problem with BMT is that it is NOT a guaranteed cure. It is extremely difficult for parents of children with Late-Infantile MLD and Juvenile MLD who already show symptoms to accept that a Bone Marrow Transplant could actually make the situation much worse for their children. Time is of the essence for BMT—early diagnosis and pre-symptomatic is ideal. This frequently means that it is the younger siblings of an affected child are the ones who benefit from this procedure as their diagnosis is made before the disease manifests itself.

About us

MLD Support Association UK was set up to bring hope to families in the fight to eradicate Metachromatic Leukodystrophy (MLD). Our aim is to provide support by way of shared information from people in similar circumstances who have already experienced the effects of the condition and/or any treatments available.

MLD Support Association UK

MLD Support Association UK is a
Registered Charity Number 1150542

Patrons
Professor Timothy M Cox, MD, FRCP, FMedSci
Suzi Digby (Lady Eatwell) OBE
Iain Stewart MP

Contact

MLD Support Association UK
Floor 5
Amphenol Business Complex
Thanet Way
Whitstable
CT5 3SB

Tel: 07977 440809
admin@mldsupportuk.org.uk