Perspectives On Medical Research
Volume 4, 1993

Contents

Update: Duchenne Muscular Dystrophy and Myoblast Transfer

Eric Dunayer

"Scientific Problems with Animal Models of Duchenne Muscular Dystrophy" (Volume 3, Perspectives on Medical Research) discussed myoblast-transfer research (both in vitro and in vivo) aimed at uncovering a treatment for Duchenne muscular dystrophy (DMD).(1) In such research, immature muscle cells (myoblasts) are injected into diseased muscle with the hope that they will fuse to the muscle's cells and produce the muscle protein dystrophin, which is lacking or dysfunctional in DMD patients. This dystrophin production may then prevent muscle necrosis, seen in DMD.

Myoblast transfer was first achieved in vitro.(2) Following this success, researchers tested the technique in nonhuman-animals. Although myoblast transfer supposedly prevented muscle necrosis in dy/ay^2j mice,(3) who ordinarily develop a fatal muscular dystrophy, pathologist Terence A. Partridge has questioned this finding. In dy/ay^2j mice, muscle necrosis has a neurologic, not muscular, cause. How, then, could this necrosis be prevented by myoblast transfer, which compensates for a muscle defect?(4) Researchers also tried the technique in mdx mice, a strain that suffers spontaneous muscle necrosis due to an absence of dystrophin. In these mice, myoblast transfer apparently restored muscle function.(2,4) Again, however, experimental validity is highly doubtful. Unlike DMD patients, mdx mice show complete, spontaneous muscle regeneration following initial muscle necrosis, with little or no permanent muscle weakness.(2,4) Because irradiation prevents this normal recovery, researchers irradiated the mice before performing myoblast transfer.(2,4) Both the disease's normal course in the mice and the irradiation, therefore, constituted undermining variables--elements entirely absent in DMD. Finally, researchers tried myoblast transfer in CXMD dogs, a strain of golden retrievers whose muscles lack dystrophin.(5) In one experiment, the dogs showed signs of rejecting the transferred myoblasts, even though the dogs were administered immunosuppressants.(5) In another experiment, the myoblasts did fuse with the abnormal muscle (likely, administering higher doses of immunosuppressants to the dogs prevented myoblast rejection); the myoblasts, however, failed to produce dystrophin.(5)

Disregarding the nonhuman-animal data's inconsistency and apparent invalidity, researchers proceeded with human clinical trials. Initially they reported encouraging outcomes.(4)

Since the publication of "Scientific Problems with Animal Models of Duchenne Muscular Dystrophy," however, the clinical results of myoblast transfer have proved contradictory and suspect. Peter Law and his colleagues have reported promising results in DMD patients receiving myoblast transfer,(6,7) but other research groups have failed to duplicate these results.(7) Further, some researchers have questioned Law's methods of data collection and reporting (for example, his acknowledged exclusion of some test results that indicated lack of improvement in DMD patients); an FDA investigation has resulted.(6,7)

Following a 1992 conference on myoblast transfer, 25 researchers in the field of muscle development and disease wrote a letter to Science urging a temporary halt to all studies involving myoblast transfer as a treatment for children with DMD. Such studies, the researchers stated, "indicate only limited survival of the implanted myoblasts and no significant improvement in the clinical status of these children." The anesthesia and immunosuppressants used in the procedure, the researchers noted, place DMD patients at unacceptable risk. They advocated that clinical trials involving myoblast transfer cease until further animal studies have supplied more data.(7)

Additional animal research, however, is unlikely to clarify the prospects of treating DMD with myoblast transfer. To date, myoblast-transfer studies in nonhuman animals have provided conflicting results compromised by species differences in immunology, muscular physiology, and pathology.

References

1. Dunayer E. Scientific problems with animal models of Duchenne muscular dystrophy. Perspec Med Res 1991;3:1-21.

2. Partridge T. Use of normal myogenic cells to repair, replace, and rescue mdx mouse muscle from necrosis, in Angelini C, Danieli GA, Fontanari D (eds): Muscular Dystrophy Research: From Molecular Diagnosis toward Therapy. New York, Excerpta Medica, 1991.

3. Law PK, Goodwin TG, Li HJ, Ajamoughli G, Chen M. Myoblast transfer improves muscle genetics/structure/function and normalizes the behavior and life span of dystrophic mice, in Griggs R, Karpati G (eds). Myoblast Transfer Therapy. New York, Plenum Press, 1990.

4. Partridge TA. Myoblast transfer, A possible therapy for inherited myopathies? Muscle & Nerve 1991;14:197-2l2.

5. Discussion of Drs. Kornegay's, Bartlett's, and Cooper's papers, in Griggs R, Karpati G (eds). Myoblast Transfer Therapy. New York, Plenum Press, 1990.

6. Thompson L. Cell-transplant results under fire. Science 1992;257:472-474.

7. Thompson L. Researchers call for time out on cell-transplant research. Science 1992;257:738.