Inherited Disorders

Many inherited disorders result from mutation of a single gene (hence, singlegene [monogenic] disorders). While individually infrequent in the population, this category as a whole contributes significantly to the chronic disease burden, and includes sickle cell anemia, hemophilias, inherited immune deficiency disorders such as adenosine deaminase deficiency, hypercholesterolemia due to defects in the LDLreceptor, and cystic fibrosis. 
In many instances singlegene disorders are a direct consequence of loss of function of the relevant protein, such that its replacement (or mere addition to the cell) would be curative. This is the most straightforward application of somatic gene therapy and may be entertained once the mutant gene has been identified and its normal counterpart isolated. Delivery of a normal factor VIII gene to a patient with hemophilia is an example. 
In some instances, the mutant protein participates more indirectly in cellular pathology, such as in sickle cell anemia where a variant globin causes hemoglobin to polymerize under low oxygen tension, thereby damaging the red blood cell. In this situation, gene transfer and expression of a normal globin chain is still expected to benefit the patient. 
In yet other instances, such as in dominantly inherited connective tissue disorders in which the presence of an abnormal molecule interferes with normal tissue development and function, only selective silencing of the mutant gene would be expected to be of benefit to the patient.
Although "gene addition" is the simplest strategy for somatic gene therapy, several practical difficulties need to be addressed. Particularly important among these is the need in many instances to deliver the appropriate gene to a specific cell type or tissue. Other challenges includes gaining access to the relevant cell type for correction, assessing the total fraction of cells in a tissue that need to be corrected, achieving the level of expression required for correction, and regulating expression of the added gene once it is transferred into appropriate target cells.

For a variety of more common diseases (e.g., coronary heart disease, diabetes), typically several genes are involved, making a single gene mechanism exceptional. Knowledge of pathophysiology is beginning to suggest how in particular instances the introduction of specific genes might reverse or retard disease processes at the cellular level. This general approach may prove effective regardless of genetic etiology and without the need to replace a single, missing gene product. For instance, in restenosis following angioplasty, local transfer into vascular cells of genes reducing proliferative and thrombotic processes might prevent reocclusion.
The possibilities for gene transfer as a treatment for common multifactorial diseases are vast. The precise approach needs to be assessed in each instance by considering how specific gene products influence cellular physiology. We can expect many different, sometimes speculative, strategies to be proposed. Each will need to be judged in comparison with conventional treatment approaches.

Some articles on applications and problems in this field:

Gene therapy for the hemophilias

Towards gene therapy of diabetes mellitus

Towards a molecular therapy for glycogen storage disease type II (Pompe disease)

Gene Therapy and the Concept of Genetic Disease    David Magnus

Prenatal gene therapy: can the technical hurdles be overcome?

Long-lasting gene repair


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