Treatment strategies for hereditary disorders

Posted by & filed under Part 02: PERSPECTIVES, Part 03: GENERAL THEMES.

Nature Reviews Genetics 7, 261-276 (April 2006)
Focus on: Monogenic disorders
Genetic medicines: treatment strategies for hereditary disorders
Timothy P. O’Connor and Ronald G. Crystal
This great review focuses on the barriers to overcome for the effective treatment of monogenic disorders in the years to come.

For more information on the treatment of inherited disorders, please see chapter 5. 
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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

One Response to “Treatment strategies for hereditary disorders”

  1. pcampeau



    The term Homo modificans is used in this chapter to describe a feature of Homo sapiens sapiens; it recognizes that human beings purposefully modify their experience. In the 20th century, one result has been an increase in the heritability of our diseases. Accordingly, the relative importance of genetic causes in human disease is relatively greater than it was in the past. As our ability to recognize and identify those diseases and their causes increases, our ability to treat them successfully should also increase.

    General principles for the treatment of genetic disease were established a generation ago. Those principles identify modalities that, in practice, modify the effect of a mutant gene in the affected individual. Although the principles of treatment are reasonably well understood, consistent and successful application of those principles in practice for many of these disorders remains elusive.

    The goal of treatment for genetic diseases, in every case, is to restore homeostasis through time and in the particular compartment relevant to the pathogenic process. Experience proves that it has been difficult with the existing modalities of treatment to reestablish normal homeostasis in most genetic diseases. Failure to do so is usually explained by the inability of the modality to penetrate the compartment where dishomeostasis begins or to introduce the process of treatment early enough to prevent deviant development and function. Measurements of the outcome of treatment undertaken over the past 15 years in three separate studies show significant progress but, where there is disappointment, it is usually because treatment does not restore homeostasis adequately.

    The basic modalities of treatment, up to now, have operated at four general levels: (1) At the clinical level are opportunities for surgical corrections and repairs. (2) At the metabolic level, it may be possible to prevent substrate accumulation and toxicity or to repair product depletion and the effects of the corresponding deficiency. (3) At the protein level, it may be possible to activate or stabilize a mutant protein with pharmacologic doses of coenzyme or replace lost function with normal protein. (4) At the cellular level, organ, tissue, or cellular transplantation/implantation may repopulate the body with integrated and regulated gene product activity. The major progress accounting for improved treatment of human genetic diseases over the past decade is explained by transplantation in its various forms.

    At present, there are no unambiguous examples of successful somatic gene therapy.

    As we proceed from structural genomics to functional genomics, the focus will shift from DNA to proteins. How a mutation affects the structure and function of a protein is already a major area of inquiry. It follows that therapies to neutralize the effect of mutation on the protein itself will be of increasing interest. Some of this knowledge will be converted through combinatorial drug design techniques into agents that fit and modify the variant protein phenotype (either structural or functional). Early work in this direction looks promising with applications to patient care.26-28

    Complex traits account for the majority of patients with genetic disease. As their pathogenic mechanisms are broken down into their components, the principles and practices developed for single-gene diseases will find new applications in the vastly larger community of patients with complex trait diseases. Again, there is reason for optimism as shown by progress with treatment of coronary artery disease over the past generation. There are thoughtful scientists who dare to pose this question with some optimism: “Heart attacks: Gone by the end of the 20th century?”6 Perhaps, then it is reasonable to expect an affirmative answer to this question: “Can we greatly improve the treatment of genetic diseases within the next quarter-century?”

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