MUSCLE COULD BE THE THERAPEUTIC TARGET IN SMA TREATMENT

A nerve-muscle coculture model (human muscle cells innervated by embry onic rat spinal cord) was used to explore the pathogenesis of spinal m uscular atrophy (SMA), Previous studies showed that myofibers from don ors with SMA type I or SMA type II (but not SMA type III) undergo a ch aracteristic degeneration 1-3 weeks after innervation (Braun et al. [1 995] Lancet 345:694-695), To determine which cells are involved in deg eneration, we cloned satellite cells and fibroblasts derived from musc le biopsies of normal (healthy) donors and donors with SMA, We show th at fibroblasts are required for successful innervation, that fibroblas ts from normal and SMA donors contribute equally well to the establish ment of cocultures, and that only SMA satellite cells are responsible for the degeneration of innervated cocultures, We succeeded in prevent ing the degeneration of cloned satellite cells from SMA donors by addi ng 50% cloned satellite cells from normal donors to the culture to mak e heteromyotubes, In mixed cocultures, after innervation, we did not o bserve degeneration. This result suggests that survival of the cocultu res depends on a message derived from the muscle cells, Consequently, we propose that therapeutic approaches for SMA that could repair (or c ompensate for) the genetic defect in muscle cells (which are otherwise much more accessible for gene therapy than neurons) might prevent mot oneuron degeneration. The role of muscle cells in the establishment an d the degeneration of neuromuscular junctions deserves further attenti on and investigation, (C) 1998 Wiley-Liss, Inc.