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Laminins play a key role in the assembly of sarcolemmal basement membranes by establishing anchors to the cell surface and underlying cytoskeleton, by polymerizing to form a cohesive scaffold, and by forming links to type IV collagen and other extracellular components. Laminin-deficient (MDC1A) congenital muscular dystrophy is caused by structural instability of the basement membrane in which absent or poorly-expressed laminin-211 is replaced by laminins-411 and -511. Laminin-411, the main compensator, is an inadequate substitute for the lost laminin because it adheres poorly to integrins and dystroglycan and cannot polymerize. The first deficiency has been repaired with miniagrin, an engineered protein that binds to the coiled-coil of laminins, anchoring it to dystroglycan. We now find that the second deficiency can be repaired with αLNNd, a protein engineered to bind to the nidogen-binding locus and enable polymerization of laminin-411, promoting its self-assembly. Transgenic αLNNd-expressing mice were bred with dystrophic dy2J (α2LN deletion, non-polymerizing) and dy3K (laminin α2 knockout) mice. The transgene was found to increase the accumulation of compensating laminins and to substantially improve hindlimb muscle histology in dy2J as evidenced by decreased myofiber fibrosis, reduced fraction of central nuclei and increased myofiber cross-sectional area. αLNNd was also found to ameliorate the severe dy3K dystrophy as seen by a ∼2.5-fold increased lifespan with increase body weight, muscle strength, and improved muscle histology. The findings support a critical role of laminin polymerization for stable scaffold structure. They also suggest a new therapeutic basis for structural repair of the human dystrophy. [Copyright &y& Elsevier]