Dietary gene therapies

Therapeutic strategies for enzyme deficiency diseases include dietary modification and potential gene therapy or direct enzyme replacement (Table 3-1). 

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. 

Until gene therapy allows substitution of the defective PAH gene with its normal counterpart in vivo, the mainstay of therapy in classic PKU is to maintain levels of phenylalanine in the blood between 3 and 12 mg/dL through dietary restriction of this essential amino acid. 

Gordeuk. V. et at F.ffect ol Irnn Chelation Therapy oil Recovery front Deep Coma in Children until Cerebral Malaria.", V, Eng.. 1. Med. 14711 November 19, 19921. Gordeuk. V.. et al. Iron Overload in Alrieti — Interaction between a Gene and Dietary Iron Content.", V. Eng. J. Med., 95 tJanuarx 9, 1992 t. 

Since each of these disorders is caused by the lack of an enzyme, scientists are trying to design a way to replace the lost activity. Oral medication will not work because enzymes are proteins. They would simply be digested, fike any other dietary protein. Enzyme replacement therapy is one approach that is being studied. This would involve periodic injections of the enzyme into the bloodstream, a treatment just fike the injection of insulin by diabetics. Enzyme replacement therapy would require a large supply of the enzyme. Eollowing the model of insulin, the gene for the enzyme could be cloned into bacteria. The bacteria would then produce the protein, which would be purified for use by humans. 

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