Hope For Duchenne Muscular Dystrophy Patients Using A Targeted Antisense Therapy

AVI-4658, a targeted antisense therapy to restore expression of dystrophin, a key protein which patients with Duchenne muscular dystrophy lack, shows promise, researchers from the Neuromuscular Centre, UCL Institute of Child Health, London, UK, wrote in the journal The Lancet.

Professor Francesco Muntoni and team wrote that approximately 1 in every 3,500 British males has Duchenne muscular dystrophy (DMD). The patient's muscle cells break down and are lost, leading to progressive muscle weakness. By the time the boy is between the age of 8 and 12 years he can no longer walk. By the time they reach late adolescence or early adulthood their condition has deteriorated so much that many die.

AVI-4658 might be an effective treatment for a considerable number of patients.

This open-label, phase 2, dose-escalation study with 19 patients was carried out at three centers - Great Ormond Street Hospital, or Children NHS Trust (GOSH), both in London, and the Royal Victoria Infirmary, Newcastle, England.

When treatment was completed, a muscle biopsy was taken from each child. The team discovered that the patients' ability to produce functional mRNA through "exon skipping' was repaired with the use of AVI-4658 - eventually allowing them to manufacture functional dystrophin protein.

The researchers said:

"Seven patients had a significant dose response, six of whom were in the two high-dose cohorts, showing restoration of dystrophin protein expression up to 18% of normal levels."

They concluded:

"On the basis of our data and recent preclinical data, we expect that extended administration of AVI-4658 at doses of 10 mg/kg or higher will result in sufficient dystrophin expression to have a positive effect on the prevention of muscle degeneration in Duchenne muscular dystrophy... AVI-4658 has the potential to ameliorate the progressive natural history of Duchenne muscular dystrophy and now needs to be investigated in clinical efficacy trials." Comment in the same journal Dr Akinori Nakamura, Shinshu University School of Medicine, Matsumoto, Japan, and Dr Shin'ichi Takeda, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan, wrote:

"The regulatory and practical (ie, scaling up) barriers to clinical use of exon-skipping therapy are much less daunting than those for gene therapy with viral vectors or cell transplantation therapy. Therefore, successful clinical trials of exon skipping therapy in patients with Duchenne muscular dystrophy could have a great effect on development of treatments for other intractable hereditary neuromuscular disorders."

"Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study"
Sebahattin Cirak*, Virginia Arechavala-Gomeza*, Michela Guglieri, Lucy Feng, Silvia Torelli, Karen Anthony, Stephen Abbs, Maria Elena Garralda, John Bourke, Dominic J Wells, George Dickson, Matthew J A Wood, Steve D Wilton, Volker Straub, Ryszard Kole, Stephen B Shrewsbury, Caroline Sewry, Jennifer E Morgan, Kate Bushby, Francesco Muntoni
The Lancet July 25, 2011. DOI:10.1016/S0140-6736(11)60756-3

Asthma Risk Lower In Breastfed Babies

Babies fed only on breast milk up to the age of six months have a lower risk of developing asthma-related symptoms in early childhood, and this appears to be independent of infectious and allergic diseases, according to a study by researchers at the Erasmus Medical Center in Rotterdam in The Netherlands that was published early online recently in the European Respiratory Journal. The researchers said their findings add support to the idea that babies in industrialized countries should be given only breast milk up to the age of six months. The research is part of the Generation R Study, which is following thousands of multi-ethnic urban children from before birth until early adulthood, to identify early environmental and genetic causes of normal and abnormal growth, development and health. Although other studies have already linked breastfeeding to asthma risk, the researchers said their findings are the first to show a link between duration of breastfeeding and number of wheezing periods. They also found that asthma-related symptoms appear earlier in children who are breastfed for fewer months or who are also given other milk or solids earlier (in the first four months). The researchers used questionnaire-gathered data to look at the effect of breastfeeding duration and the introduction of other liquid and solid food on 5,368 children. The data told them whether the children had been breastfed in their first 12 months of life, when they stopped having breast milk, and whether they were given any other milk or solids, and if so, when. Another set of data came from questionnaires filled in later, when the children reached 1, 2, 3 and 4 years of age. This told them about diseases and illnesses, including asthma-related symptoms such as wheezing, shortness of breath, dry cough and persistent phlegm. The results showed that: Compared to children who were breastfed for 6 months or more, children who had never received breast milk had an increased risk of wheezing, shortness of breath, dry cough and persistent phlegm in their first 4 years. The strongest associations were with persistent phlegm (children who were never breastfed had 1.5 times higher risk of this symptom), and wheezing (1.4 times higher risk if never breastfed).
Being fed solids or other milk as well as breast milk during the first four months were linked to higher risk of wheezing, shortness of breath, dry cough and persistent phlegm in preschool years compared to having only breast milk in the first four months.
Adjusting for potential influencers, the links between breastfeeding and asthma-related symptoms could not be explained by eczema, but partly by lower respiratory tract infections. The researchers concluded that: "Shorter duration and non-exclusivity of breastfeeding were associated with increased risks of asthma-related symptoms in preschool children. These associations seemed at least partly explained by infectious but not by atopic mechanisms." Lead author Dr Agnes Sonnenschein-van der Voort, who also works in the Department of Paediatrics in the Division of Respiratory Medicine at the Erasmus Center, told the press that although more studies should be done to look at whether breastfeeding protects against asthma later in life: "These results support current health policy strategies that promote exclusive breastfeeding for 6 months in industrialised countries." "Duration and exclusiveness of breastfeeding and childhood asthma-related symptoms." A.M.M. Sonnenschein-van der Voort, V.V.W. Jaddoe, R.J.P. van der Valk, S.P. Willemsen, A. Hofman, H.A. Moll, J.C. de Jongste, and L. Duijts Eur Respir J erj01781-2010; published ahead of print 20 July 2011: doi:10.1183/09031936.00178110 Additional source: European Lung Foundation.

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