Myopathy Clinical Trial
Official title:
A Comparative Study of Strategies for Management of Duchenne Myopathy in Assiut University Children Hospital
1. Comparing different lines of treatment of Duchenne Myopathy (DM) and assessment of new
lines of treatment (mesenchymal stem cell, phosphodiesterase inhibitors) in reducing the
impact of disability in the patients with Duchenne Myopathy and slowing the progression
of cardiomyopathy
2. Upsetting and implementation of the best treatment plan for those children with Duchenne
myopathy which is suitable for the available resources in Assiut University Children
Hospital
Duchenne muscular dystrophy(DMD) is the most commonly inherited pediatric muscular disorder.
It is an X-linked genetic progressive and degenerative myopathy characterized by progressive
weakness, which can lead to loss of motor functions in puberty as well as cardiac,respiratory
involvement and premature death. The disease is one of a group of myopathies that differ
depending on the degree of severity and the affected muscle types. It occurs at a rate of
approximately 1:3500 male births and arises due to spontaneous mutations in the Dystrophin
gene (locus Xp21.2); 65% of causative mutations are intragenic deletions, 6-10% are
intragenic duplications and 30-35% are point mutations (along with other sequence
variations). The disease is caused by a deficiency of Dystrophin or the synthesis of
functionally impotent Dystrophin, a critical protein component of the Dystrophin glycoprotein
complex acting as a link between the cytoskeleton and the extracellular matrix in skeletal
and cardiac muscles. A consequence of Dystrophin glycoprotein complex inefficiency is muscle
fragility, contraction-induced damage, necrosis and inflammation.
Glucocorticoid can prolong ambulation by 2 to 3 years, reduce scoliosis, and temper pulmonary
and cardiac decline in the second decade of life. However, glucocorticoids causes well-known
side effects, which are intolerable in more than 25% of patients. Thus, a disease-specific
treatment is a major unmet need. Investigators have proposed various possibilities for the
beneficial effects of corticosteroid based mainly on observations in mouse models of muscular
dystrophy and on a limited number of studies in patients.
These possibilities include
1. Reducing cytotoxic T lymphocytes
2. Increasing Laminin expression and myogenic repair
3. Retarding muscle apoptosis and cellular infiltration
4. Enhancing Dystrophin expression
5. Affecting neuromuscular transmission
Some patients with Duchenne Myopathy treated early with steroids appear to have an improved
long-term prognosis in muscle, myocardial outcome, and can help keep patients ambulatory for
more years than expected without treatment. One protocol gives prednisone (0.75 mg/kg/day)
for the 1st 10 days of each month to avoid chronic complications. Deflazacort, administered
as 0.9 mg/kg/day, may be more effective than prednisone. The American Academy of Neurology
and the Child Neurology Society recommend administering corticosteroids during the ambulatory
stage of the disease.Published recommendations suggest starting therapy between 2 and 5 years
of age in boys whose strength has plateaued or is declining, but earlier treatment may be
more beneficial.
Skeletal muscle has a great capacity to regenerate following muscle wasting caused by trauma
or disease.This regenerative potential is attributed primarily to skeletal-muscle resident
stem cells called satellite cells. In Duchenne Myopathy, satellite cells are exhausted
following many rounds of muscle degeneration and regeneration. Hence, satellite cells and
their progeny (myoblasts) have been considered as a promising candidate for cell replacement
therapy for DMD and other types of muscle disease. Small quantities of adult stem cells exist
in most tissues throughout the body where they remain quiescent for long periods of time
prior to being activated in response to disease or tissue injury. Adult stem cells can be
isolated from cells of the hematopoietic, neural, dermal, muscle and hepatic systems. Adult
stem cells give rise to cell types of the tissue from which they originated, but according to
scientific reports, they can differentiate into lineages other than their tissue of origin,
e.g. transplanted bone marrow or enriched hematopoietic stem cells (HSCs) were reported to
give rise to cells of the mesoderm, endoderm and ectoderm.
Two main types of stem cells usually derived from adult bone marrow are HSCs and mesenchymal
stem cells (MSC). They can sometimes be obtained from fat, skin, periosteum, synovial
membrane and muscle as well. MSCs are multipotent and capable of differentiating into several
connective tissue types including osteocytes, chondrocytes, adipocytes, tenocytes and
myoblasts. They can also impose an additional anti-inflammatory and paracrine effect on
differentiation and tissue regeneration via cytokine pathways and have anti-apoptotic
features. These genetically determined pluripotent cells may be easily isolated from bone
marrow because they have membrane proteins (marker called cluster of differentiation (CD34 +)
and specific marker STRO-I). Compared with pluripotent embryonic stem cells or induced
pluripotent stem cells, mesenchymal stem cell have a greater biosafety profile and lower risk
of tumorigenicity, and perhaps that is why numerous -mesenchymal stem cell based therapies
have made it to the clinical trial stage. Stem cell based therapies for the treatment of
Duchenne Myopathy can proceed via two strategies.
The first is autologous stem cell transfer involving cells from a patient with Duchenne
Myopathy that are genetically altered in vitro to restore dystrophin expression and are
subsequently re-implanted. The second is allogenic stem cell transfer, containing cells from
an individual with functional dystrophin, which are transplanted into a dystrophic patient.
Intramuscular route of administration can be considered most appropriate as muscular
dystrophy is primarily a muscle disease. The cells can be injected in several points in the
muscle alternatively they can be injected in the motor point of the muscle. A motor point is
the point at which the motor branch of the innervating nerve enters the muscle. It is the
point with the highest concentration of motor endplates and myoneural synapses. Due to high
numbers of neuromuscular junctions at this point, a muscle contraction can be easily elicited
using minimal electric stimulus. Motor points can therefore be identified as superficial
points directly over the points on the muscles with help of external electrical stimulation.
Limitation of this method is that only superficial muscles can be stimulated using this
method.
In an open study, Sharma and colleagues demonstrated the efficacy of autologous bone marrow
mononuclear transplantation by intramuscularly to patients with Duchenne Myopathy, Becker
muscular dystrophy and limb girdle muscular dystrophy. However, they did not provide the
molecular diagnosis of these dystrophies. No significant adverse events were noted. An
increase in trunk muscle strength was seen in 53% of the cases, 48% showed an increase in
upper limb strength, 59% showed an increase in lower limb strength and approximately 10%
showed improved gait. Eighty seven percent of 150 patients had functional improvement upon
physical examination and electromyogram studies after 12 month.
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