The evolution of humans included introduction of an inactivating deletion in the CMAH gene, which eliminated biosynthesis of N-glycolylneuraminic acid from all human cells. Here we show that this human-specific sialylation change contributes to the marked discrepancy in phenotype between the mdx mouse model for Duchenne muscular dystrophy (DMD) and the human disease. Despite lacking dystrophin protein in almost all muscle cells, mdx mice show slower development, relative to overall lifespan, or reduced severity of a number of clinically relevant disease phenotypes compared to DMD patients. This is especially true for loss of ambulation, cardiac and respiratory muscle weakness, and loss of lifespan, all major phenotypes contributing to DMD morbidity and mortality. All these phenotypes occur at an earlier age or to a greater degree in mdx mice bearing a human-like mutation in the mouse Cmah gene. Altered phenotypes correlate with changes in two mechanisms; reduced strength and expression of the dystrophin-associated glycoprotein complex and increased activation of complement. Activation of complement may be driven by the increased expression of anti-Neu5Gc antibodies in Cmah−/−mdx animals and ultimately by uptake of N-glycolylneuraminic acid, a foreign glycan in humans and Cmah-deficient mice, from dietary sources. Cmah-deficient mdx mice represent a new small animal model for DMD that better approximates the human glycome and its contributions to muscular dystrophy.

Recent studies have shown that a number of genes that are not mutated in various forms of muscular dystrophy may serve as surrogates to protect skeletal myofibers from injury. One such gene is Galgt2, which is also called cytotoxic T cell GalNAc transferase in mice. In this study, we show that Galgt2 overexpression reduces the development of dystrophic pathology in the skeletal muscles of mice lacking ␣ sarcoglycan (Sgca), a mouse model for limb girdle muscular dystrophy 2D. Galgt2 transgenic Sgca ؊/؊ mice showed reduced levels of myofiber damage, as evidenced by i) normal levels of serum creatine kinase activity, ii) a lack of Evans blue dye uptake into myofibers, iii) normal levels of mouse locomotor activity, and iv) near normal percentages of myofibers with centrally located nuclei. In addition, the overexpression of Galgt2 in the early postnatal period using an adeno-associated virus gene therapy vector protected Sgca ؊/؊ myofibers from damage, as observed using histopathology measurements. Galgt2 transgenic Sgca ؊/؊ mice also had increased levels of glycosylation of ␣ dystroglycan with the CT carbohydrate , but showed no up-regulation of ␤ , ␥ , ␦ , or sarcoglycan. These data , coupled with results from our previous studies , show that Galgt2 has therapeutic effects in three distinct forms of muscular dystrophy and may , therefore , have a broad spectrum of therapeutic potential for the treatment of various myopathies.

Vaccination has become an important therapeutic approach to the treatment of Alzheimer's disease (AD), however, immunization with Aβ amyloid can have unwanted, potentially lethal, side effects. Here we demonstrate an alternative peptide-mimotope vaccine strategy using the SDPM1 peptide. SDPM1 is a 20 amino acid peptide bounded by cysteines that binds tetramer forms of Aβ 1-40 -and Aβ 1-42 -amyloid and blocks subsequent Aβ amyloid aggregation. Immunization of mice with SDPM1 induced peptide mimotope antibodies with the same biological activity as the SDPM1 peptide. When done prior to the onset of amyloid plaque formation, SDPM1 vaccination of APPswePSEN1(A246E) transgenic mice reduced amyloid plaque burden and Aβ 1-40 and Aβ 1-42 levels in the brain, improved cognitive performance in Morris water maze tests, and resulted in no increased T cell responses to immunogenic or Aβ peptides or brain inflammation. When done after plaque burden was already significant, SDPM1 immunization still significantly reduced amyloid plaque burden and Aβ 1-40/1-42 peptide levels in APPswePSEN1(A246E) brain without inducing encephalitogenic T cell responses or brain inflammation, but treatment at this stage did not improve cognitive function. These experiments demonstrate the efficacy of a novel vaccine approach for Alzheimer's disease where immunization with an Aβ 1-40/1-42 amyloidspecific binding and blocking peptide is used to inhibit the development of neuropathology and cognitive dysfunction.