The ability to reprogram fibroblasts into cardiomyocytes has many therapeutic implications. Half of the cells in the heart are fibroblasts, so the ability to call upon this reservoir of cells already in the organ to become beating heart cells has tremendous promise for cardiac regeneration. Introducing the defined factors, or factors that mimic their effect, directly into the heart to create new heart muscle would avoid the need to inject stem cells into the heart and all the obstacles that go along with such cell-based therapies. In this study Deepak Srivastava and colleagues endeavoured to reprogram committed fibroblasts to cardiomyocytes and started with a pool of 14 candidate cardiomyocyte-inducing factors. Cardiomyocyte induction of mouse neonatal cardiac fibroblasts was observed 1 week after retroviral transduction in 1.7% of the cells. After fine-tuning the cocktail to combine crucial cardiac-inducing factors and exclude inhibitory or ineffective factors, a best set was identified, consisting of the transcription factors Gata4, Mef2c, and Tbx5. Use of this trio of factors increased the efficiency of direct cardiomyocyte induction to a remarkable 20%. Although induced cardiomyocytes (iCMs) displayed expression of cardiac proteins within a week, their further maturation occurred in the weeks thereafter: sarcomeric organization and contractility increased and electrical properties “matured.” As expected for true reprogramming, epigenetic resetting of a selected group of genes to that of a cardiomyocyte state was evident. Furthermore, by using inducible lentiviral expression, the authors showed that iCMs were stable for at least 1 week after the three factors were switched off. Most interestingly, in comparison to reprogramming of somatic cells to induced pluripotent stem cells (iPSCs), lineage reprogramming (both for cardiomyocytes as well as neuronal cells) appears to be rapid and relatively much more efficient. Srivastava and colleagues propose that the difference in efficiencies may be explained by the fact that the cells are directly converted to cardiomyocytes without reverting to precardiac developmental stages such as mesoderm or cardiac progenitor cells. Direct reprogramming has not yet been done in human cells and the hope is still to find small molecules, rather than genetic factors, that can be used to direct the cell-fate switch. There will be obvious important clinical implications if generic and robust iCM production protocols can be developed and applied for adult human cells. Although many hurdles remain to be overcome in order to establish effective cell-based therapies patient-derived iCMs may be used in the future for treatment of heart disease and would offer advantages over iPSC-derived cardiomyocytes.

Masaki Iedasend, Ji-Dong Fu, Paul Delgado-Olguin, Vasanth Vedantham, Yohei Hayashi, Benoit G. Bruneau, Deepak Srivastavasend. Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell, 142(3): 375-386, 6 August 2010

Duchenne muscular dystrophy (DMD) is due to the absence of dystrophin, which is in itself linked to abnormalities in the DMD gene. However, traces of residual dystrophin and revertant muscle fibres can be found in more or less large numbers in muscle biopsies of patients. In this paper, a British team has demonstrated that of 63 biopsies from DMD patients, 47% were revertant fibres, 32% showed residual traces of dystrophin, 15% were revertant fibres and showed traces of residual dystrophin and 36% did not contain any dystrophin. No correlation between the presence of revertant fibres or residual dystrophin was identified with the performance of patients (assessed by the Motor Ability Score) or their response to corticosteroids. Finally, a second biopsy performed in nine patients, approximately eight years after the first biopsy, showed no increase in the number of revertant fibres or residual dystrophin in contrast to that commonly observed in mdx mice. These results should facilitate the implementation and evaluation of clinical trials based on the restoration of dystrophin expression.

Arechavala-Gomeza V, Kinali M, Feng L, Guglieri M, Edge G, Main M, Hunt D, Lehovsky J, Straub V, Bushby K, Sewry CA, Morgan JE, Muntoni F. Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: implication for clinical trials. Neuromuscul Disord. 2010 May;20(5):295-301. Epub 2010 Apr 14.

Glycogen storage disease type II or Pompe disease is characterized by muscle weakness, cardiomyopathy and frequent respiratory failure. It is due to the lack of an enzyme, alpha-glucosidase (GAA) or acid maltase, responsible for the degradation of glycogen to glucose in cells. This results in excessive accumulation of glycogen in the lysosomes of cells of different organs. Enzyme replacement therapy is currently the main treatment. In this study, Dutch researchers describe the results of a randomized, placebo-controlled Phase III clinical trial conducted by Genzyme. The trial assessed the efficacy of a recombinant human GAA (alglucosidase alfa or Myozyme) for the treatment of late forms of Pompe disease. Ninety patients aged 10-70 years, ambulatory and without invasive ventilation, received intravenous Myozyme (20mg/kg body weight) or placebo every two weeks for 78 weeks in eight centres in the U.S. and Europe. The two main criteria for evaluating the effectiveness of treatment were the distance covered during a 6-minute walking test and the value of the vital capacity. After 78 weeks, treated patients showed an improvement of 28.1 m (+ / -13.1 m) in the 6-minute walking test and an improvement of 3.4% (+ / -1.2%) in the vital capacity, despite the advanced stage of the disease, while placebo patients continued to deteriorate. The number of reported side effects was similar in both groups (treated and placebo).

van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010 Apr 15;362(15):1396-406.

Myasthenia gravis is an autoimmune neuromuscular disease due to an acquired immunological abnormality and characterized by fluctuating muscle weakness and great fatigue. Conventional treatment is based on anticholinesterase plus drugs to block, if any, the erratic immune system (corticosteroids, immunosuppressants). Two recent randomized controlled studies have tried unsuccessfully to prove the superiority of mycophenolate mofetil (CellCept®), an immunosuppressant used in preventing organ transplant rejection, over prednisone in the treatment of myasthenia. In this study, American research scientists have tried to determine whether the failure of these studies could be due to their short duration (three months) and an unexpected beneficial effect of prednisone. The authors analyzed the fate of 78 of the 102 patients from the two short-term studies who extended the treatment beyond 78 months. These patients had been treated with mycophenolate mofetil alone or in combination with prednisone. The results show that the percentage of patients showing improvements in their condition began to increase only after 6 months of treatment to reach 80% of those followed after 24 months. No significant difference was shown between treatments with mycophenolate mofetil alone or in combination with prednisone. The dose of prednisone was reduced after 12 months, 75% of patients taking doses lower than 7.5 mg/day and 54.5% even having stopped after 25 months. This retrospective analysis shows that mycophenolate mofetil begins to improve myasthenic events after 6 months of treatment, whether it is used in combination with prednisone or as monotherapy.

Hehir MK, Burns TM, Alpers J, Conaway MR, Sawa M, Sanders DB. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve. 2010 May;41(5):593-8.