Metachromatic Leukodystrophy Research

Currently there is no cure for MLD, however in recent years we have seen an increased interest by researchers to specifically study MLD. Several different areas are being explored both in the United States and abroad. Recent progress is very encouraging and we saw European Phase I Clinical Trials start for Enzyme Replacement Therapy in early 2007. These trials reached the Phase II 52-week point in September 2008. A US Natural History Study was approved by the FDA in February, 2008 and a US-based Clinical Trial is anticipated for 2008. See details here.

Bringing a new therapy or drug to market is a lengthy and detailed process - see here for details of a typical time line. Please remember it takes many years of research and trials along with millions, if not tens of millions of dollars to gain approval of a new treatment.

There are four primary lines of research into a cure for MLD. Each of these is briefly described below along with a summary of the lab(s) working on that line of research. See this link for more details of each of the therapies.

This type of therapy involves replacing diseased cells with new disease free cells. Generally this is accomplished by a transplant. The three forms being study are:

Bone Marrow or Stem Cell Transplants (BMT/SCT)
In this type of transplant a person with MLD undergoes "conditioning" to kill off their own bone marrow and then bone marrow (stem cells) from a donor, who is not affected with MLD, is injected into a person. If all goes well and the transplant is successful (engrafted), the new bone marrow cells produced contain the previous missing enzyme. The long term effects of a successful BMT/SCT are still being studied. This procedure does not reverse the damage already done by MLD and whether it stops or slows future damage is under investigation. The most success has been seen in affected siblings who are not yet showing physical signs of MLD. The The University of MN/Fairview Medical Center is one of the pioneering centers involved in Stem Cell Transplants and research.

Umbilical Cord Blood Transplant
This type of transplant is the same as a BMT/SCT except the stem cells are obtained from umbilical cord blood. To learn more about umbilical cord blood banks click here. These stem cells are not as mature and do not contain the antibodies that can lead to a potentially life threatening complication of transplant called graft vs. host. Again, the most promising results have been in seen in people who are not showing significant signs of MLD (pre-symptomatic). Dr. Joanne Kurtzberg at Duke University has been pioneering this line of research.

Oligodendrocyte Research
Research is being done by Dr. Joanne Kurtzberg and Fellows at Duke University on exploring the feasibility, safety and efficacy of targeted cell therapy using umbilical cord blood derived cells called oligodendrocytes. These cells have the potential ability to repair damaged done by MLD by becoming other types of cells. (They become and replace the damaged cell). Oligodendrocytes are cultured from fresh cord blood and expanded in cultures. Animal studies are in progress to determine the best route of delivery, engraftment potential and ability of these cells to facilitate neural repair. If these studies prove safe and feasible, Phase 1 human safety trials will be planned. The hope is to some day be able to transplant these cells directly into the brain or spinal column and have them do their repairing work.

Dr. Gieselmann's lab in Germany is also doing similar research on MLD. This lab was the first to develop the MLD mouse model.

Creation and Study of Cell Lines
Dr. Paul Orchard, Dr. Larry Charnas, and Jakub Tolar of the University of Minnesota are researching the possibility of creating a MLD cell line from MSC and MAP C cells. This will enable a more in-depth study of MLD disease human cells and a better understanding of the disease. It will also provide a way for researchers to see how MLD human cells behave when the different therapies are applied.

In this therapy, the missing enzyme (Arylsulfatase-A) is replaced by a man-made enzyme that is injected into the MLD affected person.

A Danish company, Zymenex (formerly known as Heme Biotech), has been pioneering this research and have created the recombinant biotech ASA enzyme called "Metazym". They started clinical trials in Europe and then sold the product to Shire HGT in early 2008.

Shire HGT of Boston, MA has shelved their internally developed ERT in favor of the purchase and ongoing test of Zymenex's Metazyme in early 2008. A US clinical trial of what they are now calling HGT-1111 is anticipated for early 2009. Details can be found here.

This therapy involves the manipulation of genes to deliver the missing ARSA enzyme. Dr. Maria Sessa, Dr. Alessandra Biffi, Dr. Luigi Naldini and their colleagues at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy are researching the efficacy and safety of hematopoietic stem cells (HSC) to deliver the therapeutic ARSA enzyme to the nervous system by the route of the blood cells.

Dr. Alessandra Biffi, M.D., reported in October 2008 success with repairing the characteristics of HSCs taken from MLD-affected mice so the HSCs could express ARSA. The repaired HSCs were successfully transplanted into the central nervous system of a a mouse model. After this treatment, the effects of MLD were corrected. Using HSCs from human MLD patients, the ARSA deficiency was successfully corrected in the HSCs. The next step is giving the treated HSCs back to a MLD patient. A HSC gene therapy clinical trial has been proposed to the Italian authorities and is expected to start by the second quarter of 2009. Similar to the successful mouse therapy the affected patients HSCs are isolated, normal ARSA gene is transplanted into the isolated HSCs, then their own corrected HSCs are transplanted back into the patient. Using the patient's own HSC should reduce or eliminate the complications of graft vs. host disease and provide a long term solution to proper ARSA expression in MLD patients.

Substrate Reduction Therapy

With MLD there is not enough ARSA enzyme present to break down all of the sulfatides produced by the body. Instead of increasing the enzyme levels, which is the goal of most other MLD therapies, substrate reduction therapy focuses on reducing the amount of sulfatide produced by the body.

A research study testing warafin as an inhibitor of sulfatide production is currently underway. Details and participation information can be found by clicking here.