Metabolic gene therapy

Gene therapy for this metabolic defect may become available within the next few years. In vitro studies have demonstrated the feasibility of retroviral-mediated gene transfer of both the El-a and E2 subunits of the branched-chain decarboxylase complex [16,18],... 

To date, cellular and gene therapy products submitted to FDA have included clinical studies indicated for bone marrow marking, cancer, cystic fibrosis, AIDS, and inborn errors of metabolism and infectious diseases. Of the current active INDs approximately 78% have been sponsored by individual investigators or academic institutions and 22% have also been industry sponsored. In addition to the variety of clinical indications the cell types have also been varied. Examples include tumor infiltrating lymphocytes (TIL) and lymphocyte activated killer (LAK) cells, selected cells from bone marrow and peripheral blood lymphocytes, for example, stem cells, myoblasts, tumor cells and encapsulated cells (e.g., islet cells and adrenal chromaffin cells). 

These are the successes there are many failures as well. More than 400 gene therapy clinical trials have been conducted, mainly on cancer, but not many cases worked. In 1999, an 18-year-old boy in Pennsylvania unexpectedly died from a reaction to gene therapy when he was treated for a metabolic disease. This trial raised many issues, and many trials with discrepancies and unreported adverse events were suspended by the FDA. The FDA has since introduced tighter controls for gene therapy trials. 

Many diseases, such as hereditary metabolic defects and tumors, can still not be adequately treated. About 10 years ago, projects were therefore initiated that aimed to treat diseases of this type by transferring genes into the affected cells (gene therapy). The illustration combines conceivable and already implemented approaches to gene therapy for metabolic defects (left) and tumors (right). None of these procedures has yet become established in clinical practice. 

Zhang YC, Atkinson MA. Gene therapy for type 1 diabetes metabolism, immunity, islet cell preservation, and regeneration. Curr Opin Endocrinol Diabetes 2004 11 91-7. 

A. OTC is a metabolic enzyme required to break down ammonia. Total lack of this enzyme leads to death shortly after birth owing to a buildup of ammonia. The partial presence of OTC also leads to accumulation of ammonia, which can be controlled by drugs and dietary intake. The genetic cause of this disease, its morbidity, and the need for rapid production of OTC by adenoviral vectors may extend the life span of OTC-deficient newborns to allow for drug treatment and dietary manipulation. Jesse Gelsinger, the 18-year-old patient who was the first patient to die on a phase I gene therapy trial, had OTC deficiency. 

The same multigenic approach can apply to cancer pharmacogenomic research, which may be especially relevant to cancer therapies that do not have an obvious candidate polymorphism in metabolism genes and do not have a major protein target, such as cisplatin-based chemotherapy and radiation therapy as well as combinatorial therapy with multiple agents. We will use cisplatin-based chemotherapy as a prototype to illustrate the application of using a pathway-based approach in pharmacogenomic studies. 

Efficacy Autologous HSC gene therapy and non- myeloablative conditioning in two conditioning in two ADA-SCID patients In both patients, the number of PBLs, serum IgM, IgA and IgG levels, mRNA expression of the ADA vector, intracellular ADA enzymatic activity in PBLs, and erythrocyte enzyme activity indicated a reconstitution of -cell functions, as well as an amelioration of the metabolic pattern. 515130... 

Insulin-dependent diabetes mellitus (IDDM) is an example of a metabolic disease under active consideration for inducible gene therapy strategies. In this disorder, inflammatory cytokines have been shown to activate apoptosis in pancreatic beta cells. Experimental studies indicate that expression of insulinlike growth factor-1 (IGF-1) can prevent the cytokine-mediated destruction of beta cells of the pancreas (Giannoukakis et al., 2001). Regulated expression of IGF-1 in human pancreatic islets, to preserve beta cell function, may be a useful approach in the treatment of certain types of diabetes (Demeterco and Levine, 2001). 

The latter studies on pDNA delivery of a therapeutic gene to treat metabolic diseases, autoimmune diseases, viral infections or cancer suggest that naked pDNA could be used for gene delivery. The advantages of this type of therapy include the simplicity of i.m. injection, the requirement for only a limited number of i.m. injections to achieve measurable serum levels of the therapeutic protein, the maintenance of stable serum levels of the protein thereby avoiding side-effects associated with bolus protein delivery and the avoidance of the use of viral vectors which pose safety concerns and which can induce anti-vector antibodies. With improvements in pDNA design and delivery, this type of gene therapy may someday prove useful for therapy of a variety of human diseases. 

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