Metachromatic Leukodystrophy

Watchlist

(log in to enable)

Retrieved

2021-01-18

Source

Wikipedia

Trials

—

Genes

ARSA, NPC1

Drugs

—

Interested in hearing about new therapies?

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

Signs and symptoms

Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.

In the late infantile form, which is the most common form of MLD (50–60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.
Children with the juvenile form of MLD (onset between 3 and 10 years of age) usually begin with impaired school performance, mental deterioration, and dementia, then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. Some patients can live for several decades after onset. A recent trend is to try to distinguish early-juvenile (ages 3–7) and late-juvenile forms of the disease. Generally early-juveniles have motor skill declines as their first symptoms while late-juveniles show cognitive declines first.
The adult form commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.

Palliative care can help with many of the symptoms and usually improves quality of life and longevity.

Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the body's sulfatide.

Causes

Diagram showing the disrupted pathway

MLD is directly caused by a deficiency of the enzyme arylsulfatase A (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. However, assay of the ARSA enzyme activity alone is not sufficient for diagnosis; ARSA pseudodeficiency, which is characterized by enzyme activity that is 5~20% of normal controls does not cause MLD. Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain (central nervous system – CNS) and the peripheral nerves (peripheral nervous system – PNS) which control, among other things the muscles related to mobility, cease to function properly.

Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. When the arylsulfatase A enzyme level is normal but the sulfatides are still high – meaning that they are not being broken down because the enzyme is not activated – the resulting disease is saposin B deficiency, which presents similar to MLD. Saposin B Deficiency is very rare, much more rare than traditional MLD. The enzyme that is present is not "enabled" to a normal level of efficiency and can't break down the sulfatides which results in all of the same MLD symptoms and progression.

A 2011 study contended sulfatide is not completely responsible for MLD because it is nontoxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.

Genetics

MLD has an autosomal recessive inheritance pattern. The inheritance probabilities per birth are as follows:

If both parents are carriers:
- 25% (1 in 4) children will have the disease
- 50% (2 in 4) children will be carriers, but unaffected
- 25% (1 in 4) children will be free of MLD – unaffected child that is not a carrier
If one parent is affected and one is free of MLD:
- 0% (0) children will have the disorder – only one parent is affected, other parent always gives normal gene
- 100% (4 in 4) children will be carriers (but unaffected)
If one parent is a carrier and the other is free of MLD:
- 50% (2 in 4) children will be carriers (but unaffected)
- 50% (2 in 4) children will be free of MLD – unaffected child that is not a carrier

In addition to these frequencies there is a 'pseudo'-deficiency that affects 7–15% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist. This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed.

For further information, see recessive gene and dominance relationship. Also, consult the MLD genetics page at MLD Foundation. [revise or delete]

Diagnosis

Clinical examination and MRI are often the first steps in an MLD diagnosis. MRI can be indicative of MLD but is not adequate as a confirming test.An ARSA-A enzyme level blood test with a confirming urinary sulfatide test is the best biochemical test for MLD. The confirming urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results.Genomic sequencing may also confirm MLD, however, there are likely more mutations than the over 200 already known to cause MLD that are not yet ascribed to MLD that cause MLD so in those cases a biochemical test is still warranted.

Newborn Screening

MLD Foundation formally launched a newborn screening initiative in late 2017. The screen development started in the early 2010s at the University of Washington Gelb Biochemistry lab. A deidentified pilot study launched in April 2016 in Washington State. Positive results led to MLD being included in the ScreenPlus identified baby research project in New York state, which is currently scheduled to launch in Q4'2020. An Expert Advisory Group (EAG) was launched in February 2020 to define the MLD NSB flow and prepare a RUSP Nomination. Seven Working Focus Groups (WFG) are supporting the EAG in their efforts. In parallel, the MLD community is organizing to support the worldwide implementation of MLD newborn screening.

Treatment

There is currently no therapy or cure for MLD in late infantile patients displaying symptoms, or for juvenile and adult-onset with advanced symptoms. These patients typically receive clinical treatment focused on pain and symptom management.

Pre-symptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either presymptomatic or displaying mild symptoms, can consider bone marrow transplantation (including stem cell transplantation), which may slow down the progression of the disease in the central nervous system. However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed. Recent success has involved stem cells being taken from the bone marrow of children with the disorder and infecting the cells with a retro-virus, replacing the stem cells' mutated gene with the repaired gene before re-injecting it back into the patient where they multiplied. The children by the age of five were all in good condition and going to kindergarten when normally by this age, children with the disease can not even speak.

Several therapy options are currently being investigated using clinical trials primarily in late infantile patients. These therapies include gene therapy, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and potentially enzyme enhancement therapy (EET).

Gene therapy was submitted to the EMA for review in December 2019. The trial sponsor has indicated they will are targeting submission for US FDA review during 1st half 2021.

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene), a gene therapy for the treatment of children with the 'late infantile' (LI) or 'early juvenile' (EJ) forms of metachromatic leukodystrophy (MLD). The active substance of Libmeldy consists of the child's own stem cells which have been modified to contain working copies of the ARSA gene. Libmeldy was approved for medical use in the EU in December 2020.

Libmeldy is indicated for use in children with the 'late infantile' or 'early juvenile' forms of MLD, who have been identified as carriers of the defective gene but have not yet developed symptoms. It is also indicated in children who have been diagnosed with the early juvenile form who have started developing symptoms but still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is a gene therapy medicinal product, for which CD34+ haematopoietic stem and progenitor cells are collected either from the patient's own bone marrow or mobilised peripheral blood. These cells are modified to insert a functional gene to produce the ARSA enzyme. When the modified cells are injected back into the patient as a one-time infusion, the cells are expected to start producing the ARSA enzyme that breaks down the build-up of sulfatides in the nerve cells and other cells of the patient's body.

Epidemiology

The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide. There is a much higher incidence in certain genetically isolated populations, such as 1 in 75 in Habbanites (a small group of Jews who immigrated to Israel from southern Arabia), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel.

As an autosomal recessive disease, 1 in 40,000 equates to a 1 in 100 carrier frequency in the general population.

There are an estimated 3,600 MLD births per year, with 1,900 alive in the US, 3,100 in Europe, and 49,000 alive worldwide with MLD.

MLD is considered a rare disease in the US and other countries.

Research

Bone marrow and stem cell transplant therapies

Several trials are underway to continue to improve the effectiveness and reduce the risks of bone marrow and stem cell transplants.

Gene therapy

(current as of January 2021)

Two different approaches to gene therapy are currently being researched for MLD.

Gene therapy with an autologous stem cell transplant – Italian researchers at the San Raffaele Telethon Institute tested a novel approach combining gene therapy with a stem cell transplant.
- Gene therapy for late infantile and early juvenile patients was approved by the European Commission in December 2020 after receiving a favorable European Medicines Agency CHMP review in October 2020. The product is being marketed in the EU as Libmeldy™. Additional information can be found on the MLD Foundation's Gene Therapy page and at the Clinical Trials.gov site.
- In November, 2020, Orchard Therapeutics acknowledged IND discussions with the FDA as the part of their effort to seek FDA approval in the USA.
- A trial for late juveniles was launched in February 2020.
- Orchard Therapeutics acquired the gene therapy IP from GSK in April 2018.
- Recruiting for the Phase I/II Clinical Trial formally started on March 24, 2010, after approval from the Italian Authorities. Recruiting the initial cohort of 8 patients was completed in mid-March 2013. The trial was to test the efficacy and safety of autologous (using the patient's own cells) hematopoietic stem cell transplantation (HSCT) after genetic modification to deliver a super-therapeutic (over-expressing) ARSA enzyme to the nervous system by the route of the blood cells. Using the patient's own stem cells with genetic correction should reduce or eliminate the complications of graft vs. host disease and provide a long-term solution to proper ARSA expression in MLD patients. Bench and animal tests showed positive results. The researchers published 2-year outcomes for the first three patients in July 2013. Results were described as promising.
- The Phase I/II clinical trial is complete. No additional patients are being recruited while the data is analyzed and work progresses to improve the manufacturability and repeatability of the technology while expansion to other geographies to increase access is being considered.
- Recruiting was completed for the 20 patient cohort in April 2015, which includes an expansion in December 2014 to add 6 additional patients.
- Inclusion criteria are pre-symptomatic late infantiles and both pre- and early-symptomatic juveniles. See details on inclusion criteria and the trial protocol here.
- The trial was at a single center at the San Raffaele Institute in Milan, Italy. All costs were to be paid by the researchers. This was a 3-year study. In March 2013, the last of the 8 primary trial patients started therapy. The trial had several compassionate access patients and ultimately was expanded to 20 patients
- In late 2013 GSK exercised its option for the San Rafaelle gene therapy technology and is working with the Milan Investigators to prepare for the next phase of study.
Intracerebral Gene therapy – A Phase I/II Clinical Trial started recruiting in Paris in late March, 2013 for an Intracerebral Gene Therapy clinical trial where special "vectors" carrying genetically modified material are directly injected into a dozen sites in the brain. The hope is that the corrected cells and the enzyme they produce will then diffuse into surrounding areas of the brain. Extensive work in the lab and some encouraging ALD studies provided the basis for this trial. This trial was subsequently terminated before completion.

Enzyme replacement therapy (ERT)