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Therapeutic Genes

Posted by Ares Wednesday, December 1, 2010

In its simplest form, gene therapy for inherited metabolic disease involves introducing a gene into a patient to express an enzyme which the patient lacks because of an inherited genetic defect. Examples of such therapy would be the replacement of phenylalanine hydroxylase in patients with phenylketonuria or the low-density lipoprotein (LDL) receptor in patients with familial hypercholesterolemia. This approach to gene therapy would be applicable to most autosomal recessive diseases and many X-linked diseases where one copy of the normal gene or
in many cases even a fraction of normal enzymatic activity is known to prevent the pathological phenotype of the disorder.

Autosomal dominant disorders would be more difficult targets for gene therapy, since simple replacement of a defective gene would not be effective, and methods to circumvent the toxic effects of the dominant products will be required.
In considering gene therapy for some metabolic diseases, however, it may not be technically feasible to introduce the normal gene into the patient or it may not be possible to introduce the therapeutic gene into enough cells in the particular tissue where enzyme activity is required. This may be particularly true when successful therapy requires genes to be plased into large number of cells within the body or into sequestered sites such as the brain. Thus, various alternative approaches to gene therapy may be considered. One alternative would be to constitute novel genetic functions to circumvent an inherited genetic defect. There are precedents for this approach in the administration of betaine to treat homocystynuria by activating alternative metabolic pathways. Another alternative would be to use gene therapy to alter the regulation of genes which are present in the body. For example, autosomal dominant diseases might be treated by inhibiting expression of a mutant allele, polygenic (multifactorial) diseases may be treated by restoring a balance between various genetic functions, and certain metabolic diseases might be treated by preventing the synthesis of metabolic precursors or inducing the elimination of toxic products. A precedent for this approach to therapy is the administration of lovastatin, which causes an increase in LDL receptor levels and, consequently, the lowering of cholesterol levels. This Approach to therapy may be increasingly important in the future as the genetic factors which regulate gene expression come to be more completely understood. Another alternative would involve using gene transfer as a form of enzyme replacement therapy. This would involve constituting expression of a gene product in one cell type with the expectation that the recombinant gene product would be secreted from these cells and taken up elsewhere in the body.
It should be noted that somatic gene therapy, as currently conceived, is not directed at repairing or replacing a defective gene in the body’s cells or in the herited genetic material. While methods for such gene replacement have been described in select animal models using techniques for homologous recombination, these technologies currently have little practical application in clinical practice.
It is apparent that the various approaches to gene therapy require in-depth understanding of metabolism and the role of metabolic pathways in health and disease. Gene therapy reprecents a form of metabolic engineering, the success of which will be dependent upon both metabolic and genetic function, For example, certain enzymes will only function in cells that provide complementary subunits, substrates, or cofactors. Thus, phenylalanine hydroxylase may only function effectively in cells that provide the tetrahydrobiopterin cofactor, and the function of one component of a multicomponent enzyme such as propionyl-CoA carboxylase-a (PCCa) requires the concomitant presence of other component such as the subunit (PCC ) to constitute the active multimer. One issue which will be particularly important in developing gene therapies is the presence of rate limiting steps on multistep pathways. For example, overexpression of methylmalonyl-CoA mutase (MCM) does not result in higher than normal rates of propionate metabolism due to limits in the rate of substrate production. It is likely that many metabolic pathways will have quantitative limitations introduced by rate-limiting processes, feedback regulation, and metabolic rigidity. It is understanding of the metabolic consequences of gene expression that will determine how much enzyme needs to be expressed in how many cells, and which organs are the appropriate target for gene therapy. These are difficult issues. It is not necessarily true, for example, that expressing lowlevel enzyme activity in a large number of cells (as is the case in many mild forms of metabolic disease) will produce the same effect as expressing high levels of enzyme activity in a small population of cells. For certain metabolic diseases, it may not be true that expressing an enzyme in a heterotopic site, distant to the site of primary pathology, will have the same biological effect as expressing the enzyme in a site where the enzyme normally functions.
Thus, the identification of genes for gene therapy requires not only cloning of disease-related genes, but also an essessment of the deficient biological function and the consequences of introducing a recombinant enzyme into pathways. It is likely that considerable basic and clinical research in metabolism as well as molecular genetics will be required to fully understand the consequences of even the most simple forms of gene therapy.



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