Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers.
Cardiovasc Res. 2010 Feb 1;85(3):444-53
Authors: Jearawiriyapaisarn N, Moulton HM, Sazani P, Kole R, Willis MS
AIMS: The cardiomyopathy found in Duchenne muscular dystrophy (DMD) is responsible for death due to heart failure in approximately 30% of patients and additionally contributes to many DMD morbidities. Strategies to bypass DMD-causing mutations to allow an increase in body-wide dystrophin have proved promising, but increasing cardiac dystrophin continues to be challenging. The purpose of this study was to determine if therapeutic restoration of cardiac dystrophin improved the significant cardiac hypertrophy and diastolic dysfunction identified in X-linked muscular dystrophy (mdx) dystrophin-null mouse due to a truncation mutation over time after treatment. METHODS AND RESULTS: Mice lacking dystrophin due to a truncation mutation (mdx) were given an arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that delivered a splice-switching oligonucleotide-mediated exon skipping therapy to restore dystrophin in mdx mice before the development of detectable cardiomyopathy. PPMO successfully restored cardiac dystrophin expression, preserved cardiac sarcolemma integrity, and prevented the development of cardiac pathology that develops in mdx-null mice over time. By echocardiography and Doppler analysis of the mitral valve, we identified that PPMO treatment of mdx mice prevented the cardiac hypertrophy and diastolic dysfunction identified in sham-treated, age-matched mdx mice, characteristic of DMD patients early in the disease process, in as little as 5-6 weeks after the initiation of treatment. Surprisingly, despite the short-term replacement of cardiac dystrophin (<1% present after 12 weeks by immunodetection), PPMO therapy also provided a durable cardiac improvement in cardiac hypertrophy and diastolic dysfunction for up to 7 months after the initiation of treatment. CONCLUSION: These results demonstrate for the first time that PPMO-mediated exon skipping therapy early in the course of DMD may effectively prevent or slow down associated cardiac hypertrophy and diastolic dysfunction with significant long-term impact.
PMID: 19815563 [PubMed - indexed for MEDLINE]
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Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers.
Chronic kidney disease: whom to screen and how to treat, part 1: definition, epidemiology, and laboratory testing.
South Med J. 2010 Feb;103(2):140-6
Authors: Brosnahan G, Fraer M
Chronic kidney disease has become a major public health problem due to its high prevalence, its exorbitant cost, and large reductions in life expectancy and quality of life of affected people. Seventy percent of cases of end-stage renal disease are due to diabetes and hypertension, conditions which are usually managed by primary care providers. Other risk factors are cardiovascular disease, obesity, smoking, family history of kidney disease, and age greater than 55 years. Patients with these risk factors should be evaluated for the presence of chronic kidney disease during their primary care visits, because effective treatments for slowing progression are available, particularly if instituted early. Chronic kidney disease can be diagnosed by simple blood and urine tests, as recommended in guidelines issued by the National Kidney Foundation. This article begins with a case vignette, representing a common clinical scenario from a general internist’s practice. We then review the definition and classification of chronic kidney disease, the epidemiology, etiology, and interconnections with cardiovascular disease. We discuss the guidelines for screening and laboratory testing, as well as the limitations of current assessment tools. A subsequent article will review evidence-based management of chronic kidney disease.
PMID: 20065899 [PubMed - indexed for MEDLINE]
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Lasofoxifene in postmenopausal women with osteoporosis.
N Engl J Med. 2010 Feb 25;362(8):686-96
Authors: Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J, Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R,
BACKGROUND: The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. RESULTS: Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. CONCLUSIONS: In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)
PMID: 20181970 [PubMed - indexed for MEDLINE]
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Lasofoxifene in postmenopausal women with osteoporosis.
