Stanford BIOC 230 - Stem cell treatment of dystrophic dogs

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Title 1References 1Title 2References 2Figure 1 Expression of wild-type dystrophin in dogs transplanted with wild-type mesoangioblasts.Stem cell treatment of dystrophic dogsArising from: M. Sampaolesi et al. Nature 444, 574–579 (2006)Human muscular dystrophies are devastating and incurable inhe-rited diseases. Hopes of progress towards therapy of muscular dys-trophies were aroused when Sampaolesi et al.1reported ‘‘extensiverecovery of dystrophin expression, normal muscle…function’’, and‘‘remarkable clinical amelioration’’ in golden retriever muscular dys-trophy dogs treated with ‘mesoangioblasts’. Here I re-examine theirresults, showing how their assessments might be flawed and theirconclusions overstated. Further studies will be required to evaluatefully the clinical potential of this work.My first concern is that control and test dogs were not matched fordisease characteristics at the start of treatment to avoid inadvertentlybiased groupings in small experimental cohorts, where extensiveindividual variations exist. Also, the authors’ evaluations were notblinded. For example, their Supplementary Videos1seem to showgreater human encouragement of treated compared with untreateddogs, so functional recovery may not be independently verifiable byviewers, especially the ‘‘striking improvement of motility’’ in theolder dogs treated with mesoangioblasts.Second, Fig. 5a of Sampaolesi et al.1indicates that muscle strengthdeclined, rather than was maintained as they imply, in the treated legsof all dystrophic dogs in which it was assessed. At later time points,strength was always less than at 5 months. Between the ages of 5 and 9months, the averaged decline in strength of the two older treated dogswas ,40% (,0.079 to ,0.048 kg21(%)), even more than the ,25%decline in the control untreated dystrophic dog over the same period.Against this real , 40% decline, purported improvements of ,50%and ,80% in treated leg-muscle strength relative to contralateral,untreated muscles of these two dogs (Fig. 5b of Sampaolesi et al.1) aremisleading and probably explained by simultaneous declines incontralateral muscle strength of ,60% and ,67%, respectively.Third, the dogs Valgus, Varus and Vaccin each received 5 3 107mesoangioblasts per treatment, but these were infused into the aorticarch of Valgus and the left femoral artery of the others. At biopsy,,30–70% of fibres in sections of Valgus’ left sartorius and gastroc-nemius muscles appeared to be dystrophin-positive (Fig. 4a ofSampaolesi et al.1), whereas the equivalent dystrophin-positive pro-portion of Varus’ left sartorius was ,0–10%, and that of Vaccin’s leftgastrocnemius was only 0–5%. Numbers of mesoangioblasts reach-ing the lower left leg from upper aortic infusion, after major systemicblood diversions2, should have been ,10 times less than from directfemoral infusion. However, no assessed muscles of Valgus hadfewer—and certainly not 10 times fewer—dystrophin-positive fibresthan corresponding muscles of Varus or Vaccin. Moreover, someof the untreated muscles of Varus and Vaccin revealed up to 50%dystrophin-positive fibres (Fig. 4a of Sampaolesi et al.1).Minimal mesoangioblast recirculation3cannot easily explain theseanomalies, whereas dystrophin-positive fibres in both treated anduntreated muscles might represent false positives or revertants4,rather than evidence of mesoangioblast engraftment. Controlbiopsies from pre-treatment and untreated dystrophic dogs4wouldhave allowed these possibilities to be differentiated. Alternatively, ifrecirculation and engraftment is responsible for similar percentagesof dystrophin-positive fibres in treated and ‘untreated’ tibialis cra-nialis muscles (Fig. 4a of Sampaolesi et al.1), then contrasting theirstrengths (Fig. 5b of Sampaolesi et al.1) is unfounded.There is an indicator of benefit arising from this trial, although itis, perhaps, due to concurrent immunosuppression rather than tomesoangioblasts. Supplementary Fig. 7 of Sampaolesi et al.1showsthat levels of the muscle-breakdown marker serum creatine kinasedecreased markedly soon after initiating immunosuppression (aspreviously seen in mdx mice5) and before injection of heterologousmesoangioblasts, whereas in the days immediately after mesoangio-blast injection, creatine kinase levels varied randomly, decreasingsubstantially ( .5,000 U) in three instances but increasing in five.This does not support the authors’ hypothesis that creatine kinasereductions demonstrate mesoangioblast reconstitution of musclefibres.Control dystrophic dogs lived, on average, 129 days longer than sixout of ten treated dogs (123 days longer than those treated withautologous mesoangioblasts). Three of the four remaining treateddogs, described as ‘‘well’’ 400 days post natal, ‘‘rapidly lost walkingability’’ when immunosuppression ceased (257 days post natal fortwo of these).Altogether, the evidence presented by Sampaolesi et al.1does notconvince me that the dogs benefited from mesoangioblast treatment;a rigorous demonstration correlating muscle function, dystrophinexpression and mesoangioblast infusion, with adequate controls,would have been helpful in this regard. It is therefore premature toconsider a clinical trial in humans as a justifiable extension of thisstudy.Allan H. Bretag11Sansom Institute, School of Pharmacy and Medical Sciences, Universityof South Australia, Adelaide, South Australia 5000, Australia.e-mail: [email protected] 3 January; accepted 17 October 2007.1. Sampaolesi, M. et al. Mesoangioblast stem cells ameliorate muscle function indystrophic dogs. Nature 444, 574–579 (2006).2. Guyton, A. C. Textbook of Medical Physiology 7th edn, 230 (Saunders, Philadelphia,1986).3. Galvez, B. G. et al. Complete repair of dystrophic skeletal muscle by mesoangioblastswith enhanced migration ability. J. Cell Biol. 174, 231–243 (2006).4. Dell’Agnola, C. et al. Hematopoietic stem cell transplantation does not restoredystrophin expression in Duchenne muscular dystrophy dogs. Blood 104, 4311–4318(2004).5. De Luca, A. et al. A multidisciplinary evaluation of the effectiveness of cyclosporine Ain dystrophic mdx mice. Am. J. Pathol. 166, 477–489 (2005).doi:10.1038/nature06437Sampaolesi et al. replyReplying to: A. H. Bretag Nature 450, doi:10.1038/nature06437 (2007)Bretag1questions our finding2that ‘‘dogs benefited from mesoangio-blast treatment’’. We believe that this scepticism is not


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