o********7
发帖数: 409 | 1 【 以下文字转载自 Medicine 讨论区 】
发信人: office2007 (2007), 信区: Medicine
标 题: 有人知道进行性肌营养不良，也叫Duchenne型DMD吗？
发信站: BBS 未名空间站 (Sat Jul 9 21:54:54 2011, 美东)
国内的小外甥很不幸的了这种病，据说没有什么特效治疗方法，不知道美国这边有没有
什么新的研究成果和疗法阿？谢谢 | q*****n
发帖数: 1035 | | o********7
发帖数: 409 | | w******y
发帖数: 4871 | 4 NOVEL THERAPIES
Gene therapy — The identification of the gene responsible for the
dystrophinopathies led to initial excitement that transfer of a functioning
dystrophin protein (whether by transplanted myoblast or direct genetic
manipulation) may provide substantial benefit to or even "cure" affected
patients. Although myoblast transfer has been attempted in humans, the
results have thus far not been encouraging [47]. However, in one patient who
received a bone marrow transplant for severe combined immunodeficiency,
donor nuclei persisted in a small number (>1 percent) of myocytes for more
than 10 years [48]. Thus, cells derived from bone marrow may serve as vector
for genetic therapies.
Preliminary clinical studies are evaluating systemic gene transfer by
intravascular administration of recombinant adeno-associated viral (rAAV)
vectors that carry microdystrophin or minidystrophin genes [49-51]. One such
study found evidence of dystrophin-specific T-cells in four of six treated
patients with DMD; the activity was unexpectedly present in two patients
before vector treatment [52]. At 90 days after treatment, there was no
evidence of transgene expression. The results suggest that cellular immunity
may be an obstacle to successful dystrophin transgene therapy. The
discovery of pre-existing T-cell immunity to dystrophin may be caused by
priming of the cellular immune system to revertant dystrophin myofibers that
express truncated dystrophin protein and are present at low levels in most
patients with DMD [53-55].
Exon skipping — Another investigational approach involves injection of
antisense oligonucleotides that induce specific exon skipping during
messenger RNA splicing, thereby correcting the open reading frame of the DMD
gene and restoring dystrophin expression [51,56-61]. This type of molecular
therapy has been validated in canine and mouse models of DMD with various
oligonucleotides that can restore dystrophin expression by inducing exon
skipping during messenger RNA splicing [59,60]. Further, in preliminary
human trials, intramuscular injection of oligonucleotides that induce
skipping of exon 51 proved to be safe and induced dystrophin synthesis
locally within the treated muscles [56,57]. Similarly, systemic weekly
subcutaneous administration of an antisense oligonucleotide was associated
with new dystrophin expression in 10 of 12 patients with DMD in an
uncontrolled trial [61]. After a 12-week extension phase, improvement in the
six-minute walk test was observed in 8 of 12 patients [61]. Additional
clinical trials are in progress.
Aminoglycosides — The gene mutation in up to 15 percent of patients with
DMD is a premature stop codon. Aminoglycoside treatment of cultured cells
can suppress stop codons by creating misreading of RNA, thereby allowing the
insertion of alternative amino acids at the site of the mutated stop codon.
In vivo gentamicin therapy in the mdx mouse resulted in dystrophin
expression of 10 to 20 percent of the levels detected in normal muscle [62].
This amount provided a certain degree of functional protection against
contraction-induced damage.
Aminoglycoside therapy has therefore been suggested as an alternative to
gene therapy. This therapy could be aimed only at the minority of patients
with DMD who have premature stop codons. In a preliminary study in four
patients, treatment with gentamicin for two-weeks did not result in the
appearance of full length dystrophin in the muscles of treated patients [63]
. Some authors, unable to reproduce the results previously published for the
mouse model of DMD, have called for more preclinical investigation of this
potential therapy [64]. A subsequent study, employing six months of weekly
or biweekly gentamicin infusions, found increased levels of dystrophin
expression compared with baseline in six of 12 patients with DMD and
premature stop codons, but no statistically significant benefit on clinical
measures of efficacy [65]. Thus, aminoglycoside therapy remains unproven for
the treatment of DMD associated with stop codons.
Ataluren — Ataluren (PTC124) is an investigational orally administered drug
being developed for the treatment of genetic defects caused by nonsense (
stop) mutations. Ataluren promotes ribosomal read-through of nonsense (stop)
mutations, allowing bypass of the nonsense mutation and continuation of the
translation process to production of a functioning protein. This approach
could benefit the estimated 10 to 15 percent of patients with DMD/BMD who
harbor nonsense (stop) mutations [66]. Encouraging results were reported in
preclinical efficacy studies, where ataluren treatment of primary muscle
cells from humans and mdx mice was associated with the production of
dystrophin [67]. However, the clinical benefit of ataluren is not yet
established.
•In January 2005, the US Food and Drug Administration (FDA) approved
an indication for ataluren in the treatment of DMD. The approval was based
upon the results of phase 1 studies in healthy adult volunteers showing that
the drug is orally bioavailable and well tolerated [68].
•In a phase 2 study of 26 boys with nonsense-mutation-mediated DMD,
increased full-length dystrophin expression was observed in vitro and in
vivo with PTC124, and serum muscle enzyme levels decreased within 28 days of
treatment [69]. However, there were only minimal changes in muscle strength
and timed functions with PTC124 treatment.
•A multicenter double-blind trial randomly assigned 174 ambulatory
males (median age 8 years, range 5 to 20) with DMD/BMD to high-dose ataluren
, low-dose ataluren, or placebo [70]. At 48 weeks, patients treated with low
dose ataluren had a mean change in the six-minute walk distance that was
approximately 29 meters higher than that for placebo group, a distance close
to the 30 meter change considered clinically significant. However, the mean
change in the six-minute walk distance for the high-dose ataluren group was
similar to that for placebo group.
Additional studies are needed to determine whether ataluren is effective for
the treatment of muscle weakness in DMD and BMD.
Creatine — Creatine monohydrate has been studied for its potential to
increase muscle strength in neuromuscular disorders and muscular dystrophies
[71-73]. In a randomized, controlled, crossover trial of 30 boys with DMD,
each participant received treatment with creatine (about 0.1 g/kg per day)
for four months and placebo for four months [74]. Creatine treatment was
associated with improved grip strength of the dominant hand and increased
fat free mass compared with placebo. The beneficial effects of creatine were
independent of steroid use. However, creatine treatment was not associated
with significant improvement on functional measures or activities of daily
living. Creatine was well tolerated with no evidence of renal or liver
dysfunction.
Another small controlled trial randomly assigned 50 boys with DMD to either
creatine 5 g/day, glutamine 0.6 g/kg per day, or placebo [75]. There was no
statistically significant benefit for either treatment group compared with
placebo as assessed by change in the modified manual muscle testing score,
the primary outcome measure [75].
In light of the limited data and apparently modest benefit attributed to
creatine in these studies, demonstration of clinically important improvement
in larger trials is needed before recommending this treatment for patients
with DMD.
Deacetylase inhibitors — Several structurally unrelated deacetylase
inhibitors (trichostatin A, valproic acid, and phenylbutyrate) can enhance
muscle differentiation [76] and increase muscle size by inducing the
expression of follistatin [77]. In addition, trichostatin A treatment
restored muscle function and morphology in dystrophin-deficient mdx mice and
in alpha-sarcoglycan-deficient mice [78]. Human trials are needed to
determine if deacetylase inhibitors are beneficial for patients with
Duchenne, Becker, or limb-girdle muscular dystrophy. (See "Limb-girdle
muscular dystrophy".)
Myostatin inactivation — Myostatin is a protein that has an inhibitory
effect on muscle growth. Mice that would otherwise express the DMD phenotype
but lack myostatin have an increased muscle mass compared to those with a
wild-type myostatin gene [79]. Antibodies to myostatin also have a
beneficial effect; treated animals have increased muscle mass, strength,
lower serum creatine kinase, and less histologic evidence of muscle damage [
80].
A myostatin mutation in a child with gross muscle hypertrophy has been
identified [81], suggesting that myostatin inactivation could be a
therapeutic target to increase muscle bulk and strength in muscle wasting
diseases such as DMD [82]. Clinical trials of myostatin inhibitors are
underway [83].
Cell therapy — The use of skeletal muscle progenitors in the treatment of
DMD and BMD is under investigation but remains experimental [47,48,84,85]. A
technique that appears particularly promising in mice involves isolating
and transplanting muscle satellite cells, a natural source of cells for
muscle regeneration [86,87].
PROGNOSIS — Among those with DMD, there may be some improvement between
three and six years of age. However, this is followed by gradual but
relentless deterioration.
In the earlier literature, progression to wheelchair confinement occurred by
the age of approximately 12 years [1]. The majority of patients with DMD
died in their late teens or twenties from respiratory insufficiency (most
commonly) or arrhythmia secondary to cardiomyopathy. In some cases, the
immediate cause of death was not apparent.
Survival, neuromuscular function, and quality of life in DMD may be
improving due to longer term treatment with glucocorticoids, advances in
respiratory care, and increased utilization of assisted ventilation [88-90].
One study prospectively followed 43 patients (ages 5 to 35 years) with DMD
during the period from 1996 to 2006 with yearly assessments [91]. The
following observations were made regarding the ages at which patients
reached milestones of disease progression:
•Lost ambulation, mean 9.4 years (range 6-15 years)
•Became electric wheelchair dependent, 14.6 years (11-28)
•Needed assistance for eating and drinking, 18.2 years (12-23)
•Began assisted ventilation, 19.8 years (14-31)
The estimated median survival was 35 years [91].
By comparison, patients with BMD typically remain ambulatory beyond the age
of 16 years and into adult life; they usually survive beyond the age of 30
years and have a mean age of death in the mid 40s [1,92,93]. The most common
cause of death is heart failure from dilated cardiomyopathy, which also
causes considerable morbidity in these patients despite their milder
skeletal muscle involvement [94]. (See "Clinical features and diagnosis of
Duchenne and Becker muscular dystrophy".)
【在 o********7 的大作中提到】
: 谢谢！
| S*****s
发帖数: 287 | 5 这个是遗传病，只能改进病人的生活质量而不能治愈。你外甥已经确诊是 Duchenne 么
？我非常希望他不是这一种，因为几种 Muscular dystrophy 里面这种最严重。希望他
能有一个幸福快乐的童年。
【在 o********7 的大作中提到】
: 谢谢！
|
|
