Investigators at Washington
University in St. Louis and St. Louis Children’s Hospital are participating in
exciting research programs aimed at new treatments for a group of very rare
conditions known as lysosomal storage diseases.
The FDA has defined a rare disease as one that occurs
in less than 200,000 people in the US. More than 6000 diseases affecting
25,000,000 people fall under this definition. Until recently, little incentive
existed for biotechnology and pharmaceutical firms to develop and/or market
treatments for rare diseases. Drugs for these conditions, while often feasible
to make, offered little prospect of recouping the enormous costs associated with
getting them on the shelf and so were labeled "orphan" drugs. In an effort to
move drug companies to "adopt" these orphan drugs, Congress passed the Orphan
Diseases Act in 1983, which provided them incentives to move forward with
getting such drugs on the market. Although this law generated some movement in
that direction, it wasn’t until almost 10 years later that companies jumped on
the bandwagon after George W. Bush signed into law 2 more bills: the Rare
Diseases Act of 2002 and the Rare Diseases Orphan Product Development Act of
2002. These measures provided significant funding to develop the infrastructure
and defray the cost necessary to jump-start the pharmaceutical engines. One
small group of "orphans" who have been readily adopted by several pharmaceutical
companies are the lysosomal storage diseases (LSDs).
What is a LSD?
A lysosome is the recycle center of the cell. Its job is to
take worn out parts of the cell and recycle them into new pieces using various
enzymes. Each enzyme is responsible for recycling a certain piece of the worn
out part in an assembly line like fashion. Unfortunately, if one enzyme fails in
the line, there is no emergency shut off switch and the worn out parts just keep
piling up until the lysosome is stuffed full, eventually causing the cell itself
to fail. When enough cells fail in the organ in which they live, the organ (such
as the brain, heart or bone) starts to fail. What organs are most affected
depends on which enzyme in the assembly line isn’t working. Since there are more
than 40 of these enzymes, there are more than 40 different LSDs. Each one is
very rare but as a group, they affect about 1 in 5000 people.
What causes a LSD?
Each enzyme has its own gene that controls its production. If
there is a genetic change or mutation in that gene, the enzyme cannot be made
properly. Most enzymes have two copies of the gene (one from each parent) so
even if one gene has a mutation, the other gene can still make the enzyme. It
takes two mutations to shut off the enzyme. Some enzymes have their gene on the
X chromosome (such as Fabry disease and Hunter syndrome). A mutation of a gene
that sits on the X chromosome affects only boys because they have only one X
chromosome.
What do LSDs do?
The problems that individuals with a LSD suffer depend on
which worn out cell part is backing up on the assembly line (called storage).
Some, such as Fabry disease, don’t show many symptoms until adulthood. Most LSDs
however begin showing signs of the disease early in childhood, often in the
first year or two of life. Children with LSDs are often short, develop coarse
facial features, have significant restriction of joint movement, may develop
mental retardation and acquire severe lung disease. Some may present with very
weak muscles and heart disease. Others have severe limb or bone pain. Many of
the LSDs are so devastating that they cause death before the age of 10 years.
Some of the more common LSDs in children are Gaucher disease, Hurler syndrome
(MPS I), Hunter syndrome (MPS II) and Pompe disease. Adults with Fabry disease
develop kidney failure and stroke.
Is there treatment?
There has been limited success in only treating the symptoms
of the disease so considerable effort has been put forth to attack the source of
the problem and replace the enzyme itself. One way to replace the enzyme is to
put a normal gene into the body that can make the enzyme. This approach can be
accomplished by giving the affected individual normal genes from the bone marrow
or blood of an unaffected person (called a bone marrow or stem cell transplant)
or by making special cells in the laboratory that contain a normal gene and
injecting them into the affected individual (gene therapy). Bone marrow
transplantation (BMT) has been successful in several LSDs and allowed long term
survival with less severe symptoms. However, there are significant risks to the
BMT procedure, it does not always work and the beneficial effects sometimes wear
off. Such problems result in a difficult choice for parents to make. Gene
therapy, which is not yet available for LSDs, may circumvent most of the
disadvantages of BMT. If successful, gene therapy should also allow treatment
for all types of LSDs. Research at a number of laboratories across the world,
including Washington University in St. Louis, should result in a trial of gene
therapy for at least one these conditions in the next few years.
Another approach to replacing the
defective enzyme is to manufacture it in a laboratory and give it directly to
the patient. This method, called enzyme replacement therapy (ERT), is now
available for several of these disorders and its availability is a direct result
of the Orphan Disease legislation mentioned above. ERT has been available for
patients with Gaucher disease for over 10 years and has provided enormous
benefit. This year the FDA approved ERT for Fabry disease and Hurler syndrome.
Clinical trials are underway or planned for Hunter syndrome, Pompe disease,
Niemann-Pick B, Marateaux-Lamy syndrome and Morquio disease. However, there are
some drawbacks to this therapy as well. The manufactured enzyme does not get
into the brain and so does not treat the mental retardation that is associated
with some LSDs. It has to be given by intravenous infusion over several hours
every one to two weeks and because these drugs are so new the true long term
benefit of ERT for these disorders remains to be seen. Finally, despite the
benefits of legislation that defrays the cost of development and allows drug
exclusivity for 7 years after its approval, yearly infusion costs for these
drugs approach or may exceed more than $200,000.
Who do I talk
to?
Because LSDs are so rare, it has
been difficult to find health care professionals knowledgeable about the
diagnosis, management and treatment of LSDs. As a result, a number of
institutions around the country have created Lysosomal Treatment Centers to
address these needs. The Washington University Lysosomal Treatment Center was
created last year in response to the need for a Center of Excellence in this
area. As part of an international storage disease collaborative study group,
Washington University has gathered physicians, health care professionals, and
scientists from across its campus under one roof to provide diagnostic and
treatment programs for all of the lysosomal storage diseases. Information about
this program can be obtained by calling the Division of Medical Genetics in the
Department of Pediatrics at St. Louis Children’s Hospital
314-454-6093.