Purkinje axons in adult mammals are generally unable to regenerate after axotomy. Our recent work has shown that over-expression of growth related genes, GAP-43 and L1, in Purkinje cells increased their axonal outgrowth into a predegenerated peripheral nerve graft, but not into a fresh graft [Zhang et al., (2005)Proc. Natl Acad. Sci. USA, 102, 14883–14888]. In the current study we investigated whether engineered expression of growth permissive molecule polysialic acid (PSA) in the glial scar or on transplanted Schwann cells could overcome the inhibitory environment and promote Purkinje axonal regeneration. A stab wound was introduced in the cerebellum of the L1/GAP-43 transgenic mice and a lentiviral vector (LV) carrying the polysialyltransferase (PST) cDNA (LV/PST) was injected into the lesion site to transduce the cells in the glial scar. Regenerating Purkinje axons were examined by calbindin immunostaining. There was increased Purkinje axonal sprouting in the area expressing high-level PSA. However, Purkinje axons were unable to grow into the lesion cavity. In the second set of experiments when LV/PST transduced Schwann cells were transplanted into the lesion site, the number of Purkinje axons growing into the transplant was nine times more than that growing into Schwann cell transplant expressing GFP two months post operation. Our result suggests that transplanted Schwann cells engineered to express PSA support axonal regeneration better than naïve Schwann cells.