Genzyme

About: Genzyme is a based out in . It is known for research contribution in the topics: Enzyme replacement therapy & Population. The organization has 3085 authors who have published 3472 publications receiving 177632 citations. The organization is also known as: Sanofi Genzyme.

Immunizing Patients With Metastatic Melanoma Using Recombinant Adenoviruses Encoding MART-1 or gp100 Melanoma Antigens

Abstract: The cloning and characterization of the genes encoding melanoma-associated antigens recognized by human T cells have opened new possibilities for the development of active immunization strategies for the treatment of patients with metastatic melanoma (1,2). Two immuno-dominant antigens, MART-1/MelanA and gp100, were recognized by the majority of tumor-infiltrating lymphocytes (TILs) obtained from HLA-A2-positive patients with metastatic melanoma (3-6). In prior studies (7-9), we have reported the initial results of immunization of patients with melanoma with immunodominant peptides obtained from the MART-1 or gp100 proteins incorporated in incomplete Freund's adjuvant (IFA) and have demonstrated that antitumor precursor cells are generated in the peripheral blood of immunized patients when comparing preimmunization and postimmunization samples. These studies suggested that improved response rates were seen when peptide immunization was followed by the administration of interleukin 2 (IL-2) (9). In murine models, immunization with recombinant adenoviruses, vaccinia viruses, and fowlpox viruses encoding model tumor antigens generated antitumor responses that were capable of significantly reducing the number of established pulmonary micrometastases (10,11). These preclinical studies have stimulated efforts to develop immunization strategies against tumor-associated antigens in humans using recombinant viruses. Adenoviruses are attractive candidates for use in the development of human vaccines and for human gene therapy because the adenovirus genome can be readily manipulated by recombinant DNA techniques and inserts of foreign genes are stably integrated [reviewed in (12,13)]. The incorporation of large DNA fragments into adenovirus requires the deletion of wild-type viral DNA sequences. Most commonly, DNA sequences from the E1, E3, or E4 regions are deleted, which results in a virus deficient in viral replication. Administration of adenoviruses has been shown to be safe, and vaccines consisting of unattenuated adenovirus have been administered to millions of military recruits over the past several decades (14,15). Recombinant adenoviruses have been used as vectors for gene therapy in patients with a variety of diseases (16-24) or as vaccines to raise cellular or antibody reactivity against infectious agents (12,13,25-27). In our own preclinical study (10), we demonstrated that immunization with a recombinant adenovirus expressing the model tumor antigen, β-galactosidase, could produce specific cytolytic T cells and could reduce established metastases in tumor-bearing mice that could be enhanced by the concomitant administration of IL-2. Thus, recombinant adenoviruses were generated expressing the MART-1 and gp100 melanoma-associated antigens and the characteristics of these viruses were determined (28). We have now conducted phase I clinical trials in patients with metastatic melanoma who received active immunization with multiple doses of these recombinant adenoviruses. The immunologic, therapeutic, and safety aspects of these immunizations in humans constitute the subject of this report.

CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy.

Abstract: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of survival motor neuron (SMN) due to mutations in the SMN1 gene. In this study, an adeno-associated virus (AAV) vector expressing human SMN (AAV8-hSMN) was injected at birth into the CNS of mice modeling SMA. Western blot analysis showed that these injections resulted in widespread expression of SMN throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including increased myofiber size and improved neuromuscular junction architecture. Treated mice also displayed substantial improvements on behavioral tests of muscle strength, coordination, and locomotion, indicating that the neuromuscular junction was functional. Treatment with AAV8-hSMN increased the median life span of mice with SMA-like disease to 50 days compared with 15 days for untreated controls. Moreover, injecting mice with SMA-like disease with a human SMN-expressing self-complementary AAV vector - a vector that leads to earlier onset of gene expression compared with standard AAV vectors - led to improved efficacy of gene therapy, including a substantial extension in median survival to 157 days. These data indicate that CNS-directed, AAV-mediated SMN augmentation is highly efficacious in addressing both neuronal and muscular pathologies in a severe mouse model of SMA.