An article from e-Medicine that describes MLD in detail (may require you to log in, but it’s free).

Enzyme replacement therapy

In 2008, Shire HGT purchased the rights to Metazym, an enzyme replacement therapy (ERT) that was initially developed by Zymenex. In February 2009, Shire announced the results of its one-year Metazym trial with 13 late infantile MLD children and noted that no motor or cognitive function effects were observed. Shire had planned to initiate a Phase 2/3 study with intravenous (IV) enzyme replacement therapy but later canceled this after concluding that the IV route of administration was not succeeding. As a result, Shire decided to suspend further development of an IV formulation of arylsulfatase A (ASA) derived from CHO cells, also known as HGT-1111.

Going forward Shire believes that direct delivery to the central nervous system (CNS) offers the best chance for development of a successful treatment for MLD. Shire plans to develop HGT-1110, a formulation of ASA derived from human cells and compatible with direct CNS delivery for MLD patients. This human cell line has been used successfully by Shire for the development of other ERTs for Hunter syndrome, Fabry disease, and type 1 Gaucher disease. Development of the HGT-1110 formulation suitable for direct delivery to the CNS is ongoing, and according to Shire’s website, it is expected to be launched in in the 2013-2016 timeframe.

Volkmar Gieselmann discusses the genetics and new forms of treatment (gene therapy and enzyme replacement therapy) being studied for metachromatic leukodystrophy in the 2008 issue of Aecta Paediatrica. Click here to read the article. Gieselmann is not an advocate of transplant for the late-infantile form of MLD based on a paper published in Bone Marrow Transplant in 2007. This paper describes a case study with only one child who was pre-symptomatic yet MLD degradation continued despite transplant. While The Evanosky Foundation disagrees with this position based on personal experience, the discussion of other treatment studies is interesting. Please note that Dr. Gieselmann held a limited number of stock options in Zymenex, which produced ASA (the enzyme required by MLD
patients) for clinical application. In 2008, Zymenex’s ASA technology was purchased by Shire, LLC. Dr. Gieselmann stated in an e-mail to The Evanosky Foundation in late 2010 that he did not exercise any of the stock options.

Duke studies new approach in fetal transplants for metabolic disorders

Duke University Medical Center is conducting a study of transplants in unborn babies that have metabolic disorders (October 2009).

“Researchers say a new development in cord blood transplants forinherited metabolic disorders may be curative for some babies who are treated while still in the womb.

Joanne Kurtzberg, M.D., professor of pediatrics and pathology and director ofthe pediatric blood and marrow transplant program at Duke University MedicalCenter, says the new approach uses a small, select number of therapeutic stemcells that have been treated to hasten and improve the process of engraftment.

Kurtzberg is formally studying the procedure in a pilot trial open to newly pregnant mothers known to be at risk for having children with lethal metabolic disorders.

Metabolic disorders - also known as lysosomal storage disorders - include several dozen rare, inherited genetic diseases marked by the absence ofspecific enzymes the body needs to break down and get rid of metabolic byproducts of energy production. Left untreated, metabolic disorders can leadto bone, brain, and central nervous system problems and early death.

For the past decade or so, physicians have experimented with cord bloodtransplants after birth as a way of treating these diseases, and in many cases,treatments have been successful. Kurtzberg says the timing of the transplant iscritical.

“The idea is to give the baby cord blood stem cells from a healthy donorthat have the potential to provide healthy genes that can replace the ones thataren’t working properly in the baby’s own cells,” says Kurtzberg.Generally, she says that the earlier the treatment, the greater the chance thedonor cells will work, so transplants before the baby is born are ideal.

The fetal transplant itself is fairly simple. After a physician diagnoses thepresence of one of the genetic diseases and the parents consent to treatment,donor cells are injected directly into the baby’s abdomen at 12 to 14 weeksinto the pregnancy. After that, there is an extended period where thetransplant needs to “take,” or engraft. At birth, the baby will betested to see if donor cells are present and if they’re already working to fixthe malfunctioning genes. If not, the baby would be eligible for a conventionaltransplant with chemotherapy within the first few weeks of life.

Kurtzberg says the trial is open to pregnant women who are at risk of having ababy with Krabbe Disease, metachromatic leukodystrophy (MLD),Pelizaeus-Maerzbacher Disease (PMD), Tay - Sachs disease or Sandoff Disease.

Donor cells will be manufactured by Aldagen, Inc., a biopharmaceutical companyin Durham and a partner in the study. Kurtzberg has no interest in the company.”

If you have any questions about the study or know a familyexpecting a child that may be affected by a metabolic disorder, please contact Michelle Gailiun at (919) 660-1306 or

Stem cell therapy


Aldagen is conducting Phase III clinical trials at Duke University on its supplemental stem cell known as ALD-101. The study will determine if this supplemental stem cell accelerates cell engraftment in children who have received umbilical cord blood transplants for inherited metabolic diseases, such as MLD. Rapid engraftment would shorten the period of time a patient would be at risk for infection and bleeding after a transplant, so it would therefore increase transplant survival rates. For more information on this clinical trial, click here.

The Evanosky Foundation is continuing to sponsor pre-clinical work at Duke University which is targeted at developing cellular therapies for treatment of children with leukodystrophies. In the coming year we expect to see initiation of a Phase I clinical trial that will administer cells intrathecally (in the spinal fluid) for children with advanced leukodystrophies. Individuals or organizations who are interested in funding this or other research should contact Bob Evanosky at The Evanosky Foundation (

We at The Evanosky Foundation understand that many families are desperate for a cure for MLD. We have one son who has been treated via stem cell transplant but we also have two other sons who have not been able to be treated. We are aware that stem cell studies are taking place around the world, but we strongly encourage you to closely investigate any potential treatment prior to considering it for your child or situation. To resolve MLD, two items must be addressed:

  1. Provide the affected individual with the arylsulfatase-A (ARSA) enzyme, since the deficiency of this enzyme causes MLD.
  2. Repair the damage that has already occurred to the brain and overall nervous system as a result of the degenerative process of MLD.

Please remember that many treatments may promise to repair the brain (issue #2), but unless the enzyme can be produced (issue #1), brain repair will have to be done continuously. For a good article on this subject, please read Stem-cell tourism troubles experts. The article Injections of Hope, published in the Washington Post in September 2008, also discusses offshore stem cell injections.

Gene therapy

For several years, the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, has been researching gene therapy as an effective treatment for MLD. The team demonstrated in previous research that they were able to use a virus to transport stem cells and ARSA (the enzyme that MLD patients are missing) to the central and peripheral nervous system. This was effective in the central and peripheral nervous system for pre-symptomatic mice as well as symptomatic animals.

As of July 2010, the team has begun recruiting for a gene therapy clinical trial in Italy for the treatment of MLD. Note that they are only accepting eight patients who are pre-symptomatic (meaning they have no symptoms) with late infantile MLD, so typically the child would have to be a brother or sister of an affect MLD child. They are also accepting children with early juvenile MLD within the first six months of displaying symptoms. Note that bisulfan, a chemotherapy drug, is required as part of the conditioning regimen. The trial will use a patient’s own cells that have been genetically corrected to produce the Arylsulfatase-A (ARSA) enzyme. All study costs will be paid for by the researchers. For more information, click here, or e-mail Dr. Alessandra Biffi at or Dr. Maria Sessa at

Other research

Many clinical trials are being conducted that, while not directly related to MLD, may be applicable to the treatment of patients with this or other leukodystrophies.

  • Researchers at the University of Rochester Medical Center have used a specific type of stem cell known as a glial cell to dramatically improve the condition of mice with a neurological condition similar to MLD. The scientists injected newborn “shiverer mice,” who have been bred with a disease of the nervous system that causes them to shake and wobble, with the stem cells. Six of the 26 mice that received the transplanted cells lived far beyond their usual lifespan, and four appeared to be completely cured. To read the complete press release dated June 4, 2008, please click here.
  • The Journal of Molecular Medicine published an article in March 2008 that described a study in which mice that received injections of the recombinant human form of arylsulfatase-A (the enzyme that MLD children are missing) actually developed antibodies against the enzyme. The enzyme was still active, but this antibody prevented the enzyme from clearing the excess sulfatides. Excess sulfatides result in nerve and myelin degeneration in MLD patients. This study is important as these types of antibodies may impact the effectiveness of enzyme replacement therapy. Click here to read the full article.
  • In January 2008, Duke University’s Vinod K. Prasad and Joanne Kurtzberg published an article in Bone Marrow Transplantation on trends in transplantation of inherited metabolic diseases. Key points included that stem cell transplantation can prolong life and improve its quality in patients with inherited metabolic diseases such as MLD. It can also provide a permanent source of enzyme replacement therapy and potential for cell regeneration or repair. The source of these stem cells is unrelated cord blood, which provides increased access to donors and is very effective, particularly when transplantation is performed in early stages. For the full article, click here.
  • In the early 2008 issue of Haematologica, Dr. N. Meuleman and colleagues in Belgium describe a reduced intensity stem cell transplant for a woman with adult onset MLD. The transplant engraftment was aided by the use of mesenchymal stromal cells (MSCs). Click here for the full article. However, in April 2008, several doctors published a response to this article, also in Haematologica, raising questions as to whether the woman cited truly had MLD. Click here to read the follow-up article.
  • Duke University is conducting a Phase I clinical trial to test feasibility of collection, preparation and infusion of a baby’s own umbilical cord blood cells if the baby is born with signs of brain injury. Babies will be followed for neurodevelopmental outcome. For more information about the neonatal hypoxic-ischemic encephalopathy study, click here.
  • For information on the FDA’s Investigational New Drug (IND) Application Process, which all new drugs and treatments must go through prior to use in humans, click here. The description is lengthy, but it will provide insight on the development and procedures involved in bringing new therapies to fruition.
  • To read a paper discussing the study of transplanted ALDH cells engrafting in multiple tissues and promoting cellular repair in damaged tissues, click here.