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Genetic Medicine: Dream, Reality or Something in Between?« Back to Volume 22, Issue 4, December 2006 - Table of Contents Genetic medicine has had its ups and downs and is often influenced more by rapid shifts in public sentiment than by scientific progress. Accordingly, a thoughtful and objective review of genetic medicine from O’Connor and Crystal is welcome and appreciated by those of us who are not familiar with the intricacies and recent progress in the field. Focusing on treatment of monogenic disorders, it examines the current status of 3 broad categories of genetic medicines: somatic stem cells, gene transfer, and RNA modification. The review begins with the challenges facing genetic medicine. The main barriers are the delivery and maintenance of new genetic information. For stem-cell therapies, the major issues involve immune surveillance against foreign cells, providing a ‘niche’ and selective advantage for the transplanted cells and controlling and coordinating the proliferation, differentiation, location and survival of the stem cells and their progeny (Figure). For gene-transfer approaches, success requires circumventing immune defenses that arise against vectors that carry the therapeutic genes, transferring the gene to a sufficient number of cells to modify the mutant phenotype, and controlling expression of the new gene. For RNA-modification therapies, the principal challenge is delivery and, to some extent, specificity. The authors stress that to overcome these challenges, it is essential to understand the target, including the molecular basis of the disorder, its mode of inheritance, the range of mutations and genotype-phenotype relationships that produce disease phenotypes, and how the manifestation of these phenotypes are influenced by age, location in the body, and modulation by other genes. The review explains and illustrates the different therapeutic approaches and defines many of the terms commonly used in the world of genetic medicine. For example, differences between commonly used viral and non-viral gene-transfer vectors and their advantages and disadvantages are defined, as are the differences between antisense oligonucleotide, RNAi, ribozyme, and trans-splicing strategies to therapeutically alter mRNA transcripts harboring disease-causing mutations. Particularly interesting is a compilation and discussion of gene-transfer trials with a cautious assessment of their success in correcting the disease phenotype. The authors seem to be critical of the lack of success in many instances, but also optimistic that much has been learned to provide a basis for future progress. With regard to future prospects, the authors ask the question: with all the human and financial resources that have focused on using genetic medicines to treat monogenetic disorders, why don’t any of the therapies that have been tried alter disease phenotypes in a reproducible, efficacious manner, without significant toxicity? Their answer is that drug development takes years, averaging 12 to 15 years from concept to government approval. They also point to large societal hurdles that result in regulatory delays as well as economic barriers that must be overcome. They emphasize that despite its attention, the genetic medicine field is still young and that while genetic medicine is simple in concept, it is challenging to make it a reality. Indeed, they underscore the fact that paths for development of ground-breaking therapies taken as standard today, such as bone marrow and internal organ transplantation, and in vitro fertilization, were littered by disappointments and nay-sayers who predicted inevitable failure. Embryonic and somatic stem cells as a source of genetic medicines. The fusion of sperm and egg gametes during human fertilization establishes a diploid zygote and initiates a series of cell divisions that result in a multicellular embryo. The blastocyst stage is characterized by the presence of a blastocyst cavity, outer cell mass and inner cell mass. Embryonic stem cells are derived from the inner cell mass of the blastocyst. Embryonic stem cells in culture are capable of self-renewal without differentiation and are able to differentiate into all cell types of the endoderm, mesoderm and ectoderm lineages using appropriate signals. In utero, the blastocyst implants and all three embryonic germ layers are formed during gastrulation. Somatic stem cells are present in many fetal and post-natal tissues. Somatic stem cells are also capable of self-renewal and, with appropriate signals, differentiate into various cell types from the organ from which they are derived. The extent to which they are capable of differentiating into cell types from alternative lineages is controversial. Reprinted with permission from: O’Connor TP, Crystal RG. Nat Rev Genet. 2006;7:261–276. Copyright © NPG. 2006. All rights reserved. Editor’s CommentThis is an excellent review for clinicians and other readers of GGH who want to catch up on the current status of genetic medicine. In most ways, the potential use of genetic medicine to treat problems of skeletal growth faces the same problems as mentioned for other areas. For instance, chondrocytes within the avascular growth plate represent a very difficult cell to target by any of the strategies mentioned in this review, as well as by more conventional therapies. There are social hurdles to developing growth-stimulating therapies in some segments of our culture, and there are enough differences between patients and animal models to make testing of new therapeutic approaches in animals challenging. Nevertheless, it seems highly likely that the general advances in genetic medicine predicted by the authors of this review will find their way to more effective ways to treat growth problems, especially in monogenetic disorders. William A. Horton, MD
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
