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S. PENN, M.D.
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
SENATE APPROPRIATIONS SUBCOMMITTEE
ON LABOR, HEALTH AND HUMAN SERVICES, EDUCATION
AND RELATED AGENCIES
FEBRUARY 27, 2001
Mr. Chairman, Ranking Member
Senator Harkin, and Members of the Subcommittee, I am Dr.
Audrey Penn, Acting Director of the National Institute of
Neurological Disorders and Stroke. I am here to discuss with you the muscular dystrophies. I have been actively involved with this group
of diseases throughout my career as a physician and scientist,
working in academia, with voluntary organizations, and at
the National Institutes of Health.
What are muscular dystrophies?
The muscular dystrophies are a group of diseases which
weaken the skeletal muscles that we use to move voluntarily.
These disorders vary in their age of onset, in severity
and in the pattern of which muscles are affected. All forms
of muscular dystrophy, however, grow worse as muscles progressively
degenerate. In some types of muscular dystrophy, the heart,
the gastrointestinal system, endocrine glands, the skin,
the eyes and other organs may be affected. All of the muscular
dystrophies are genetic disorders, although the types of
inheritance vary, and Duchenne muscular dystrophy, the most
common and best known of the childhood muscular dystrophies,
often arises from new mutations.
Can we treat muscular dystrophies?
Research has revealed most-but not yet all-of the gene
defects that cause the different forms of muscular dystrophy.
Unfortunately, the life expectancy and quality of life for
people with muscular dystrophy have not improved substantially
since those discoveries. There is still no specific treatment
that can stop or reverse the progression of any form of
muscular dystrophy. For Duchenne muscular dystrophy, corticosteroids
may help, but have side effects that can be especially troubling
with children. Symptomatic treatment, though not able to
stop the disease process, may improve the quality of life
for some people with muscular dystrophies, through physical
therapy, wheelchairs and braces used for support, corrective
orthopedic surgery, and drugs.
The failure so far to produce a definitive therapy for
any form of muscular dystrophy reflects the difficulty of
the problems that we must confront to cure these diseases.
Some of these problems are unique to a particular type of
muscular dystrophy, some common to all muscular dystrophies,
and others are shared by many genetic disorders. The National
Institute of Neurological Disorders and Stroke (NINDS) and
the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS) lead efforts of several components
of NIH against these diseases. The shared responsibility
recognizes the value that various medical specialties and
disciplines bring to research and treatment. The muscular
dystrophies affect many aspects of physiology, benefit from
a wide range of fundamental biological research, and require
exploration of diverse diverse strategies for treatment.
What is most encouraging is the range of scientific approaches
that research is bringing to bear on these diseases. Molecular
biology has given us a foothold to understand what goes
wrong. To examine the list of therapies being explored for
the muscular dystrophies is tantamount to taking a tour
through the most active frontiers of modern medicine, including
gene therapy, cell replacement, and innovative approaches
to drug development.
Time will not allow me to describe all forms of muscular
dystrophy. I will discuss three common types-myotonic muscular
dystrophy, fascioscapulohumeral (FSH) muscular dystrophy
and Duchenne/Becker muscular dystrophy- and try to make
some general points along the way.
Myotonic muscular dystrophy
Myotonic muscular dystrophy (MMD) is probably the most
common adult form of muscular dystrophy, partly because
people with this disorder can live a long life, with variable
but slowly progressive disability. Myotonia refers to impaired
muscle relaxation which is associated with MMD along with
muscle wasting and weakness. This form of muscular dystrophy
affects many body systems in addition to skeletal muscles.
These include the heart, endocrine organs, eyes, and gastrointestinal
Myotonic muscular dystrophy follows an autosomal dominant
pattern of inheritance. This means that the disorder can
occur in either sex when a person inherits a single defective
gene from either parent. The gene defect that causes MMD
is a triplet repeat expansion in the untranslated region
of a gene that encodes a protein kinase (DM-PK). To attempt
to translate this into English: the inherited gene defect
arises from a long repetition of a three-letter "word" in
the part of the genetic code that carries the instructions
for making a protein. The protein is one of a class called
"kinases" that help regulate the function of other proteins.
In this case the "word" is not in the part of the gene that
specifies the makeup of the protein itself, but in a region
that may help control when the gene is turned on and off.
We don't yet understand how this genetic defect leads to
muscle degeneration, but the "triplet repeat" mechanism
has now been found in at least 15 other disorders. Scientists
have found some clues, both for myotonic dystrophy and triplet
repeat disorders in general, and research is continuing.
The fact that the repetition in the genetic code tends to
get longer with each generation explains the phenomenon
of "anticipation" in which the disease shows itself earlier
and more severely in each generation.
Facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy (FSHD) initially
affects muscles of the face (facio), shoulders (scapulo),
and upper arms (humeral) with progressive weakness. Symptoms
usually develop in the teenage years. Life expectancy is
normal, but some affected individuals become severely disabled.
The pattern of inheritance is, like myotonic muscular dystrophy,
autosomal dominant, but the underlying genetic defect is
poorly understood. Most cases are associated with a deletion-that
is, a missing piece of chromosome-near the end of chromosome
#4. These deletions don't appear to disrupt a particular
gene, but may affect the activity of nearby genes. This
complicates the search for the relevant gene and suggests
a novel mechanism may be involved.
In recent months, NIAMS has led NIH in a number of important
steps to stimulate and support further work on this poorly
understood form of muscular dystrophy. These include:
Research conference: In
May 8-9 of 2000, the NIAMS, together with the NINDS, the
NIH Office of Rare Diseases, the FSH Society, Inc., and
the Muscular Dystrophy Association of America, co-sponsored
a scientific conference on the cause and treatment of FSHD.
Researchers from the United States, Canada, Europe, South
America, and Asia met on the NIH campus in Bethesda, Maryland,
to share their latest findings and identify exciting directions
for future studies of this disease. The recommendations
that emerged from the conference fall into several categories,
including: efforts to enhance our understanding of the molecular
processes and tissue changes associated with FSHD; ways
to explore possible therapies to treat the disorder; and
strategies to promote the establishment of population-based
studies of the disease, as well as needed research resources.
NIH is using these recommendations as a guide in developing
new program initiatives related to FSHD and other muscular
dystrophies. A summary of the Workshop is available
on the NIAMS web at: www.nih.gov/niams/reports/fshdsummary.htm.
Research registry: In
September of 2000, the NIAMS and the NINDS funded a research
registry for FSHD and myotonic dystrophy. The long-term
goal of the registry is to facilitate research in FSHD and
myotonic dystrophy by serving as a liaison between families
affected by these diseases who are eager to participate
in specific research projects, and investigators interested
in studying these disorders. The registry, based at the
University of Rochester, will recruit and classify patients,
and store medical and family history data for individuals
with clinically diagnosed FSHD and myotonic dystrophy. Scientists
will be provided with statistical analyses of the registry
data, as well as access to registry members who have agreed
to assist with particular research studies. The national
registry will serve as a resource for scientists seeking
a cure for these diseases, in addition to enhancing research
to understand what changes occur in muscular dystrophy.
Research solicitations: In
November of 2000, the NIAMS and the NINDS jointly issued
a request for applications for exploratory research on FSHD.
This announcement is designed to encourage research proposals
using creative, novel, potentially high risk/high payoff
approaches that could produce innovative advances in this
field. Successful projects may include feasibility studies,
clinical protocol planning, and efforts to incorporate new
disciplines and technologies into the study of FSHD. In
developing this solicitation, the NIH built on the insights
we gained from the scientific conference cited above. Based
on that conference, we have focused this new request for
research proposals on issues related to improving our understanding
of the origins of this disease and how to characterize its
molecular basis. Among other areas, such projects could
include studies looking at changes in muscle as FSHD develops;
exploring the role of inflammation in this disease; and
creating new models of FSHD that could facilitate the eventual
development of effective therapies.
In January of 2001, NIAMS
and NINDS partnered again to issue a program announcement
with funds set aside to support research on understanding
and developing therapies for the muscular dystrophies, including
FSHD. This solicitation is described in the following discussion
of Duchenne muscular dystrophy discussion.
and Becker muscular dystrophy
Duchenne muscular dystrophy
(DMD) is the most common childhood form of muscular dystrophy,
affecting approximately 1 in 3,000 male births. About one
third of cases reflect new mutations and the rest are familial.
Because inheritance is X-linked recessive, DMD affects primarily
boys, though girls and women who carry one defective gene
may show some mild symptoms.
DMD is a particularly devastating
and lethal form of muscular dystrophy. When the body's attempts
to regenerate muscle cannot keep up with the destructive
process, muscle wasting and progressive weakness result.
DMD usually becomes evident when children begin to walk.
Boys typically require a wheelchair by age 10 to 12, and
usually die in late teens or early 20's. Becker muscular
dystrophy (BMD) is a less severe but closely related disease.
DMD results from an absence of the protein dystrophin, and
BMD reflects a partly functional version of the same protein.
Research conference: To
explore what NIH can do to develop effective therapies for
DMD and BMD, the NINDS, the NIAMS, and the NIH Office of
Rare Diseases (ORD), working together with the Parent Project
for Muscular Dystrophy held a "Workshop on Therapeutic Approaches
for Duchenne Muscular Dystrophy" on May 15th
and 16th, 2000, on the NIH campus in Bethesda,
Maryland. An international group of experts participated
in this meeting along with representatives from U.S. and
European muscular dystrophy associations and NIH staff.
On May 17th, following the Workshop, the scientific
organizers, topic leaders, and NIH program directors met
to summarize the discussion and formulate future research
priorities. A summary of the workshop is posted on the NINDS
websites at: www.ninds.nih.gov/news_and_events/dmdmtngsummary.htm.
Understanding the disease:
More than 15 years ago, researchers supported by the
NIH and the Muscular Dystrophy Association identified the
gene for dystrophin that, when defective, causes DMD and
BMD. The identification of the dystrophin gene stimulated
research that provided new insights and directions for research
on the biology of muscle and the mechanisms of disease,
as evident in thousands of high quality scientific publications
and several promising leads for developing new therapies.
One challenge the dystrophin
gene presents is its enormous size. The gene is the largest
gene yet identified in humans. Most vectors (usually modified
viruses) available for gene replacement cannot incorporate
a gene of this magnitude. The size probably also contributes
to the high rate of new mutations in the gene and to the
large number of different mutations that can occur within
the gene. Definitive therapy may require precise knowledge
of the particular gene defect in each patient.
The dystrophin protein was
unknown before the discovery of its link to DMD. Subsequent
studies have revealed that dystrophin is part of a complex
structure involving several other protein components. The
"dystrophin-glycoprotein complex" helps anchor the contents
of muscle cells through the cells' outer enclosing membrane
to the material in which muscle cells are embedded. Defects
in this assembly lead to structural problems that can disrupt
the integrity of the outer membrane of muscle cells, resulting
eventually in degeneration. One of the most remarkable spin-offs
from the elucidation of the complex has been clarification
of the interrelationships among DMD and other forms of muscular
dystrophy. Several other forms of muscular dystrophy, whose
relationships to DMD were obscure, result from mutations
in other protein components of the same dystrophin-glycoprotein
complex. These include several forms of limb girdle muscular
dystrophy, named for the characteristic pattern of muscle
weakness. Research to more fully understand the normal and
abnormal functions of the dystrophin complex, and of other
proteins closely related to dystrophin, is ongoing, and
evidence is accumulating that these proteins play important
roles in the brain as well as in muscles.
approaches: Several new approaches have emerged for
developing therapies to stop or reverse muscle degeneration
in Duchenne muscular dystrophy. All of these strategies
rely upon increased understanding of the underlying biology
of the disease. However, one point made at the May workshop
is the extent to which novel therapeutic strategies for
DMD arise from research that is not focused on muscular
dystrophy, muscle biology, or even therapeutics in general.
Logically, the simplest approach
to treating DMD might seem to be to supply a good copy of
the defective gene. An important advantage in studying DMD
is the availability of the mdx mouse which is a
useful model of the human disease. Results in mice with
the same gene defect as DMD show that modified virus "vectors,"
such as the adeno-assocated virus, can carry the therapeutic
genes into muscle cells and partially reverse the disease.
Recent experiments have also shown that a genetically engineered
"mini-dystrophin," while much smaller than the natural form,
seems able to carry out its essential functions. However,
considerable advances are needed to make gene replacement
workable for children with MD. The technology of gene replacement
is just beginning to yield clinical success in some of the
simplest diseases to treat. Treating DMD presents special
problems not only because of the large size of the gene,
but also due to the need to deliver the gene reliably and
safely to muscle cells throughout the body. Improving the
delivery of genes to muscle, optimizing the control elements
that regulate the activity of therapeutic genes, and minimizing
immunological and other potential safety problems are on-going
areas of research. The first preliminary gene replacement
trials for any form of muscular dystrophy have been designed
by MDA for a form of limb girdle muscular dystrophy caused
by a defect in a component of the dystrophin-glycoprotein
Several other approaches to
counteracting the gene defect, besides gene transfer by
viral vectors, also show promise for DMD. The use of "naked
DNA" is one approach under investigation for several diseases
that may be applicable to DMD. Another approach uses chimeraplasts.
These specifically designed synthetic molecules are hybrids
of DNA and RNA that can guide the muscle cells' own repair
machinery to correct some types of defect in the dystrophin
gene. "Antisense" nucleotides are another type of synthetic
molecule that has therapeutic potential. These molecules,
which are designed to bind specifically to certain parts
of genetic material, alter how the cells' internal machinery
reads a gene to make protein, thus compensating for certain
types of defects in dystrophin. Another strategy uses aminoglycoside
antibiotics. Some children with DMD (perhaps 15%) carry
a mutation in the dystrophin gene that creates an erroneous
DNA code signal to stop making the protein. Dr.
Sweeney, who will also testify today, did experiments in
mice with the same types of errors in dystrophin and found
that antibiotics can cause the protein synthesizing machinery
to ignore stop signals and allow muscle cells to make enough
dystrophin. Gentamicin, an antibiotic of this type, is now
being tested in clinical trials for DMD in children.
Finally, drug therapy for
DMD has also been a focus of research efforts. One approach
has used high-throughput screening (HTS) to try to find
drugs that increase the muscle production of another protein,
utrophin, that can help compensate for the loss
of dystrophin. High throughput screening employs robotics
and miniaturized assays (tests) to screen thousands of chemical
compounds quickly to find leads for further drug development.
Other pharmacological research areas of continued interest
for DMD relate to the use of corticosteroids in the disease
and to strategies informed by increased understanding of
immunology and its relation to DMD.
noted above, in January 2001, NINDS and NIAMS issued a PA-S
(program announcement with set-aside) entitled "Therapeutic
and pathogenic approaches for the muscular dystrophies"
to encourage research in areas highlighted as priorities
at the DMD and FSHD workshops and in areas important for
other forms of muscular dystrophy. The PA-S, unlike a regular
PA, sets aside funds ($5 million) for the purpose of this
research. Unlike an RFA (request for applications), this
mechanism does not restrict researchers to a single deadline
for proposals. Unsuccessful applicants are encouraged to
reapply after improving their proposals based on the suggestions
of scientists on peer review panels.
Several other actions of NINDS,
NIAMS and other components of NIH address priorities for
muscular dystrophy research that also have implications
for other disorders. These include extensive efforts, through
workshops, solicitations, and other actions, to promote
new technological approaches, such as gene replacement,
and to encourage exploratory grants from researchers not
currently working in the field. Planned workshops will also
focus on issues such as review of steroids for treatment
of DMD and clinical trial design for testing of these drugs
and issues in screening of newborns for eventual identification
of DMD when a treatment is available. NINDS has also placed
an increased emphasis on expediting clinical trials for
neurological disorders. In addition to grant mechanisms
for pilot trials and planning of large trials, the Institute
is enhancing its ability to work with researchers to design
and conduct clinical trials. NIAMS is also supporting planning
grants for clinical trials, including one on myotonic dystrophy.
In recent years, NIAMS and
NINDS have also worked together to strengthen NIH Intramural
research in muscle biology and disease. The Institutes have
recruited outstanding scientists to lead research programs
in this area. One consequence, for example, is that the
resources of the NIH Intramural program have been used to
expedite clinical trials of gentamicin therapy of DMD and
to discuss the implications of findings so far with this
The muscular dystrophies impose
enormous burdens on people with these disorders and on their
families. We at NIH recognize the need to target increased
efforts against the muscular dystrophies. We are doing so
through the workshops, then following up with targeted solicitations
for applications, including set-aside funds designed to
recruit new investigators to the field, and through other
efforts in both extramural and intramural programs that
I have cited above. The promising opportunities for developing
therapies build upon what we have learned about these disorders,
and we must continue to learn more even as we move toward
testing the best candidate therapies. It is also worth noting
that the therapeutic strategies we are now investigating
arose from research not targeted to these diseases, so we
must maintain a broad front of progress in neuroscience,
muscle disorders, and biology generally.
we at the NIH want to recognize the contributions of the
foundations represented here today-the Muscular Dystrophy
Association, which for years with the tireless efforts of
Jerry Lewis has fostered research in muscular dystrophy
and other neuromuscular diseases, and the Parent Project,
which has brought a renewed sense of urgency to the field.
The NINDS stands ready and able to work in partnership with
these organizations and others in the U.S. and abroad to
take the lead in a new strategy that will build on all we
have learned in the past 15 years and bring effective treatment
for muscular dystrophy patients. We appreciate your efforts
in increasing funding for NIH overall and the NINDS in particular,
and we dedicate ourselves to the task of putting this money
to the best possible use in helping patients with these
Mr. Chairman, I appreciate
the opportunity to discuss these disorders, which have long
been a major concern of mine, and I am pleased to respond
to any questions you may have.
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