BACKGROUND:  Systemic lupus erythematosus (SLE or lupus) is a disease characterized by the production of autoantibodies that react with native cells and tissues, causing inflammation, pain, and damage throughout the body. Increased production of IgG in SLE causes the precipitation of immune complexes in the kidney, resulting in irreversible renal damage and failure. There is no known definitive cure for SLE, and treatment is relegated to symptomatic relief of inflammation flare-ups and to non-antigen specific immunosuppression. Non-steroidal anti-inflammatory drugs and anti-malarials are used to treat milder forms of SLE, though corticosteroids and immunosuppressants are used in more severe cases. However, the efficacy of immunomodulating drugs is limited by the increased risk of infection in lupus patients, while corticosteroid therapy is also limited by its side effects, such as obesity, diabetes, and osteoporosis. There is an estimated 1.5 to 2 million Americans with lupus who will benefit from therapeutics that intervene at the gene product level and interrupt the pathogenic process.

INNOVATION:  UCLA investigators have generated a gene construct and product for use in gene vaccination of SLE. Investigators have assembled a gene coding construct that codes for both a region of a human IgG and pCons, a synthetic peptide that is able to induce immune tolerance in mice affected with a SLE-like disease. This gene product has an Ig-like structure, which is processed by the endocytic machinery of antigen presenting cells. After the construct is inserted into a plasmid, mice and human B lymphocytes as well as dendritic cells can be easily transfected. This allows for a specific tolerogenic immune response leading to relevant reduction of disease activity and significant increase of survival in experimental animals.

POTENTIAL APPLICATIONS 

• Induce immune tolerance through ex vivo transfection of gene construct.
• Gene vaccination protocols for tolerogenic immunization.

ADVANTAGES

• Specificity of the gene construct/product circumvents the systemic side effects associated with current therapies.
• The efficiency of the procedure in inducing regulatory circuits of the immune system may lead to long-term curative effects.
• The schedule of drug administration (single or multiple doses) is more tolerable than current immunosuppressive and anti-inflammatory therapies.

DEVELOPMENT-TO-DATE:  Investigators have shown that kidney damage can be suppressed in mice through this gene construct that makes CD4+ T cells hyporesponsive to antigenic stimulation. Animal experiments have shown that the gene transfer of the construct reduces hyperglobulinemia and suppresses IgG overload, thus delaying renal disease.

Reference: UCLA Case No. 2007-251