News in Muscular Dystrophy

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2010 NEWS

FEBRUARY

4 - (Molecular Therapy 2010;18(2):386–393) Complete Genetic Correction of iPS Cells From Duchenne Muscular Dystrophy

Yasuhiro Kazuki, Masaharu Hiratsuka, Masato Takiguchi, Mitsuhiko Osaki, Naoyo Kajitani, Hidetoshi Hoshiya, Kei Hiramatsu, Toko Yoshino, Kanako Kazuki, Chie Ishihara, Shoko Takehara, Katsumi Higaki, Masato Nakagawa, Kazutoshi Takahashi, Shinya Yamanaka and Mitsuo Oshimura - Japan

Human artificial chromosome (HAC) has several advantages as a gene therapy vector, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including the regulatory elements. Induced pluripotent stem (iPS) cells have great potential for gene therapy, as such cells can be generated from the individual's own tissues, and when reintroduced can contribute to the specialized function of any tissue. As a proof of concept, we show herein the complete correction of a genetic deficiency in iPS cells derived from Duchenne muscular dystrophy (DMD) model (mdx) mice and a human DMD patient using a HAC with a complete genomic dystrophin sequence (DYS-HAC). Deletion or mutation of dystrophin in iPS cells was corrected by transferring the DYS-HAC via microcell-mediated chromosome transfer (MMCT). DMD patient- and mdx-specific iPS cells with the DYS-HAC gave rise to differentiation of three germ layers in the teratoma, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice from mdx-iPS (DYS-HAC) cells were produced and DYS-HAC was detected in all tissues examined, with tissue-specific expression of dystrophin. Therefore, the combination of patient-specific iPS cells and HAC-containing defective genes represents a powerful tool for gene and cell therapies.

4 - Bringing down the barriers in translational medicine for inherited neuromuscular diseases.

4 - Evaluation of Skeletal and Cardiac Muscle Function after Chronic Administration of Thymosin beta-4 in the Dystrophin Deficient Mouse

JANUARY

12 - Cytokinetics Announces Positive Data From Phase I Clinical Trial of CK-2017357: Statistically Significant Increases in Muscle Force Production Demonstrated During Treatment With Novel Skeletal Muscle Activator

12 - (International Journal of Cardiology, 2009) Relationship of natriuretic peptide and transthoracic echocardiographic findings in 135 subjects with muscular dystrophy

Miyuki Kawakubo, Nobusada Funabashi, Maiko Takahashi, Makoto Sueishi, Yasufumi Motoyoshi, Takashi Mikata, Idai Uchida, Takehiro Asakawa, Riyo Takahashi, Midori Takamatsu, Yukie Matsuoka, Masaaki Minegishi, Hideki Naga, Rei Yajima, Akihisa Kataoka, Kwangho Lee, Issei Komuro - Japan

Purpose: To examine the usefulness of plasma atrial (ANP) and brain natriuretic peptide (BNP) levels and transthoracic echocardiogram (TTE) findings in predicting left ventricular (LV) dysfunction in muscular dystrophies (MD).

Materials and methods: 135 MD subjects (83 Duchenne MD (DMD), all males, mean age 22 ± 7 years, 20 Becker MD (BMD), all males, 45 ± 16 years, 21 limb-girdle MD (LGMD), 14 males, 52 ± 13 years, and 11 facioscapulohumeral MD (FSHD), all males, 58 ± 13 years) underwent TTE and measurement of BNP and ANP.

Results: In DMD, TTE revealed asynergy of the LV posterior-wall (72%), interventricular septum (IVS) (29%) and LV apex-wall (24%); in BMD subjects: TTE revealed asynergy of LV posterior-wall (50%) and IVS (25%); in LGMD and FSHD subjects: TTE revealed asynergy of LV posterior-wall (33 and 27%, respectively). LV end-diastolic (LVDdI) and end-systolic diameter index (LVDsI) were significantly larger in DMD than FSHD, and LV ejection fraction (LVEF) was significantly lower in DMD than LGMD and FSHD. In DMD, when LVEF was > = 35%, BNP and ANP levels remained low, but when LVEF < 35%, BNP and ANP levels showed steep increase. Relationship between LVEF and BNP or ANP levels was curvilinear (R² = 0.69 and 0.55, respectively, p < 0.001) using following equation: BNP = 673491×EF^− 2.897, ANP = 5716.6 × EF^− 1.422, respectively. When LVDdI > = 40 mm/m² or LVDsI > = 35 mm/m², LVEF < = 35%, plasma BNP and ANP levels increased steeply and the relationship between LVDdI, LVDsI, or LVEF and plasma BNP or ANP levels was curvilinear.

Conclusion: In DMD, LVEF was significantly lower, asynergy of LV posterior-wall was more frequent and BNP and ANP levels were dramatically higher when LVDdI > = 40 mm/m², LVDsI > = 35 mm/m² or LVEF < 35%.

9 - (PNAS, 2010) Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy

Jérémy Fauconnier; Jérôme Thireau; Steven Reiken; Cécile Cassana; Sylvain Richarda; Stefan Matecki; Andrew R. Marks; Alain Lacampagne - France

Patients with Duchenne muscular dystrophy (DMD) have a progressive dilated cardiomyopathy associated with fatal cardiac arrhythmias. Electrical and functional abnormalities have been attributed to cardiac fibrosis; however, electrical abnormalities may occur in the absence of overt cardiac histopathology. Here we show that structural and functional remodeling of the cardiac sarcoplasmic reticulum (SR) Ca²⁺ release channel/ryanodine receptor (RyR2) occurs in the mdx mouse model of DMD. RyR2 from mdx hearts were S-nitrosylated and depleted of calstabin2 (FKBP12.6), resulting in “leaky” RyR2 channels and a diastolic SR Ca²⁺ leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the Ca²⁺ channel stabilizer S107 (“rycal”) inhibited the SR Ca²⁺ leak, inhibited aberrant depolarization in isolated cardiomyocytes, and prevented arrhythmias in vivo. This suggests that diastolic SR Ca²⁺ leak via RyR2 due to S-nitrosylation of the channel and calstabin2 depletion from the channel complex likely triggers cardiac arrhythmias. Normalization of the RyR2-mediated diastolic SR Ca²⁺ leak prevents fatal sudden cardiac arrhythmias in DMD.

News in Muscular Dystrophy

Purpose: To examine the usefulness of plasma atrial (ANP) and brain natriuretic peptide (BNP) levels and transthoracic echocardiogram (TTE) findings in predicting left ventricular (LV) dysfunction in muscular dystrophies (MD).

Conclusion: In DMD, LVEF was significantly lower, asynergy of LV posterior-wall was more frequent and BNP and ANP levels were dramatically higher when LVDdI > = 40 mm/m2, LVDsI > = 35 mm/m2 or LVEF < 35%.

Conclusion: In DMD, LVEF was significantly lower, asynergy of LV posterior-wall was more frequent and BNP and ANP levels were dramatically higher when LVDdI > = 40 mm/m², LVDsI > = 35 mm/m² or LVEF < 35%.