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Treatment of Genetic Diseases

Treatment of Genetic Diseases


Mendelian genetic diseases are caused by single mutations in single genes. Although only 2% of human diseases can be attributed to these disorders, they affect millions worldwide, with often devastating consequences. They may be lethal in childhood. Examples are muscular dystrophy, cystic fibrosis, Huntington disease, sickle cell anemia, and lysosomal storage diseases, such as Gaucher disease.

Because of their wide impact, their treatment has been at the forefront of medical technology. Traditionally, treatment has been based on knowledge of disease biochemistry and pharmacology. The recent identification and cloning of the disease-causing genes, however, has sparked the development of new approaches—including gene therapy, enzyme replacement, and nonsense suppression for genetic diseases.

The Biochemical Pharmacology Discussion Group of the New York Academy of Sciences met on December 2, 2003, to discuss new treatments for hemophilia, muscular dystrophy, and lysosomal storage diseases. The discussion, held at the Academy, considered therapies in the early research stage, as well as those in clinical use and clinical trials.

Use the tabs above to view the meeting report and multimedia presentations.

Web Sites

American Society of Gene Therapy (ASGT)
Established in 1996, the largest medical professional organization representing researchers and scientists dedicated to discovering new gene therapies. Its official journal is Molecular Therapy.

Center for Jewish Genetic Diseases
Sponsored by Mount Sinai School of Medicine, a focus on those diseases for which screening is available. Gaucher and Tay-Sachs disease both occur more frequently among Ashkenazi Jews than in the general population.

Cystic Fibrosis Foundations
The foundation's online "information center" has links to research, treatment centers, and legislative action.

Genetics & Public Policy Center
Funded by the Pew Charitable Trusts and a part of the Phoebe R. Berman Bioethics Institute at Johns Hopkins University, the Center offers a useful page on the "regulatory climate" surrounding issues related to human cloning and genetic disease.

Human Genome Project Information
"Genetic disease information—pronto!" Turn here first for FAQs on genetics disorders, as well links to current discussion of research, ethics, and pharmaceuticals.

Lysosomal Storage Disease Network
A network of clinicians, researchers, and hospitals, with directions to treatment centers. Its site is now adding educational resources as well.

Muscular Dystrophy Association
The health agency perhaps more familiar to many Americans from its telethons, it also maintains extensive resources on neuromuscular diseases. Its site includes publications, video, and expert responses on diseases and gene therapies.

National Hemophilia Foundation
An extensive "info center" on bleeding disorders, including news, legislative updates, public education, a directory of treatment centers, and current guidelines on therapy.

National Organization of Rare Disorders
The online resource for rare disorders, including a searchable database, news, fact sheets for physicians, and a collection of speeches and policy briefs. Researchers can turn here for assistance with grants, fellowships, and requests for proposals. A wider audience will appreciate the organization's message: "out of the darkness, into the light."

Parent Project: Muscular Dystrophy
"Leading the Duchenne muscular dystrophy community," this advocacy site addresses emotional issues as well as a range of concerns for treatment and legislative action.

A World of Genetics Societies
A handy portal to the American Society of Human Genetics, the Genetics Society of America, the American College of Medical Genetics, the American Board of Medical Genetics, the American Board of Genetic Counseling, the Association of Professors of Human and Medical Genetics, and the International Federation of Human Genetics Societies.

Journal Articles

The molecular medicine paradigm

Lukacs, G. L., & P. R. Durie. 2003. Pharmacologic approaches to correcting the basic defect in cystic fibrosis. N. Engl. J. Med. 349: 1401-1404.

Vasudevan, S., & S. W. Peltz. 2003. Nuclear mRNA surveillance. Curr. Opin. Cell Biol. 15: 332-337.

Vasudevan, S., S. W. Peltz, & C. J. Wilusz. 2002. Non-stop decay—a new mRNA surveillance pathway. Bioessays 24: 785-788.

Wilschanski M., Y. Yahav, Y. Yaacov, et al. 2003. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N. Engl. J. Med. 349: 1433-1441.

Wilusz, C. J., W. Wang, & S. W. Peltz. 2001. Curbing the nonsense: the activation and regulation of mRNA surveillance. Genes Dev. 15: 2781-2785. FULL TEXT


Herzog, R. W., & K. A. High. 1998. Problems and prospects in gene therapy for hemophilia. Curr. Opin. Hematol. 5: 321-326.

Larson, P. J., & K. A. High. 2001. Gene therapy for hemophilia B: AAV-mediated transfer of the gene for coagulation factor IX to human muscle. Adv. Exp. Med. Biol. 489: 45-57.

Manno, C. S., A. T. Chew, S. Hutchinson, et al. 2003. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101: 2963.

Lysosomal storage diseases

Barton, N. W., R. O. Brady, J. M. Dambrosia, et al. 1991. Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med. 324: 1464-1470.

MPS disease

Achord, D. T., F. E. Brot, C. E. Bell, and W. S. Sly. 1978. Human beta-glucuronidase: in vivo clearance and in vitro uptake by a glycoprotein recognition system on reticuloendothelial cells. Cell 15: 269-278.

Birkenmeier, E. H., M. T. Davisson, W. G. Beamer, et al. 1989. Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J. Clin. Invest. 83: 1258-1266.

Brot, F. E., J. H. Glaser, K. J. Roozen, et al. 1974. In vitro correction of deficient human fibroblasts by beta-glucuronidase from different human sources. Biochem. Biophys. Res. Commun. 57: 1-8.

Kakkis, E. D., J. Muenzer, G. E. Tiller, L. Waber, et al. 2001. Enzyme-replacement therapy in mucopolysaccharidosis I. N. Engl. J. Med. 344: 182-188.

Sly, W. S., B. A. Quinton, W. H. McAlister, & D. L. Rimoin. 1973. Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J. Pediatr. 82: 249-257.

Snyder, E. Y, R. M. Taylor, & J. H. Wolfe. 1995. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374: 367-370.

Watson, G. L, J. N. Sayles, C. Chen, et al. 1998. Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus. Gene Ther. 5: 1642-1649.

Tay-Sachs and other diseases

Abe, A., J. Inokuchi, M. Jimbo, et al. 1992. Improved inhibitors of glucosylceramide synthase. J. Biochem. (Tokyo) 111:191-196.

Barranger, J. A., & E. O'Rourke. 2001. Lessons learned from the development of enzyme therapy for Gaucher disease. J. Inherit. Metab. Dis. 24(S2): 89-96.

de Duve, C. 1983. Lysosomes revisited. Eur. J. Biochem. 137: 391-397.

Desnick, R. J. 2001. Enzyme replacement and beyond. J. Inherit. Metab. Dis. 24: 251-265.

Hers, H. G. 1963. alpha-Glucosidase deficiency in generalized glycogenstorage disease (Pompe's disease). Biochem. J. 86: 11-16.

Kaback, M. M. 2001. Screening and prevention in Tay-Sachs disease: origins, update, and impact. Adv. Genet. 44: 253-265.

Muscular dystrophy

Barton, E. R., L. Morris, A. Musaro, et al. 2002. Muscle-specific expression of insulin-like growth factor-I counters muscle decline in mdx mice. J. Cell Biol. 157: 137-148.

Barton-Davis, E. R., L. L. Cordier, D. I. Shoturma, et al. 1999. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J. Clin. Inves. 104: 375-381.

Bogdanovich, S., K. J. Perkins, T. O. Krag, & T. S. Khurana. 2003. Therapeutics for Duchenne muscular dystrophy: current approaches and future directions. J. Mol. Med. 81 (Dec 12).

Cordier, L., A. A. Hack, M. O. Scott, et al. 2000. Rescue of skeletal muscles of g-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. Molec. Ther. 1: 119-129.

Scott, J. M, S. Li, S. Q. Harper et al. 2002. Viral vectors for gene transfer of micro-, mini-, or full-length dystrophin. Neuromuscular Disord. 12: S23-S29.

Sweeney, H. L., & E. R. Barton. 2000. The dystrophin-associated glycoprotein complex: what parts can you do without? Proc. Natl. Acad. Sci. (USA) 97: 13464-13466. FULL TEXT

van Deutekom, J. C., & G. J. van Ommen. 2003. Advances in Duchenne muscular dystrophy gene therapy. Nat. Rev. Genet. 4: 774-783.


Emerson, C. P., & H. L.Sweeney. 1997. Methods in Muscle Biology (Methods in Cell Biology, Vol. 52). Academic Press, San Diego.

High, Katherine A., & Harold R. Roberts, Eds. 1995. Molecular Basis of Thrombosis and Hemostasis. Marcel Dekker, New York.

Scriver, Charles R., Arthur L. Beaudet, William S. Sly, & David Valle, Eds. 1995. Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York.

Smith, Alan E. 1976. Protein Biosynthesis. Chapman & Hall/CRC, Boca Raton, FL.



Marla Weetall, PhD

PTC Therapeutics
email | publications

H. Lee Sweeney, PhD

University of Pennsylvania School of Medicine
email | web site | publications


Katherine Ann High, MD

University of Pennsylvania /
Children's Hospital of Philadelphia
email | web site | publications

Katherine Ann High is Howard Hughes Medical Institute Investigator, William H. Bennett Professor of Pediatrics, and professor of medicine and pathology at the University of Pennsylvania, where she has been on the faculty since 1992. She has been an attending physician at the Hospital of the University of Pennsylvania since 1996. From 1985 until 1991, she was assistant and associate professor of medicine and pathology at the University of North Carolina at Chapel Hill. Among her numerous awards and honors, she received the National Hemophilia Foundation Researchers of the Year Award in 2000.

High has served on many education panels, chaired scientific societies, and study sections. She is on the editorial board of seven journals and consultant to numerous biotechnology and pharmaceutical companies. She holds several patents and has submitted two Investigational New Drug (IND) applications. Her academic training includes a fellowship in hematology at Yale University School of Medicine and an internship at North Carolina Memorial Hospital. She received her MD at the University of North Carolina School of Medicine and her undergraduate degree in chemistry from Harvard College.

Stuart W. Peltz, PhD

PTC Therapeutics
email | web site | publications

Stuart W. Peltz president and CEO of PTC Therapeutics, co-founded the company in 1998. He leads all activities of the company, from research to fund-raising. Peltz has published widely and serves on NIH and American Cancer Society review committees. He is also on the board of the Biotechnology Council of New Jersey.

Peltz's expertise is in the area of mRNA turnover. He and colleagues developed the first biochemical assays to study the regulation of mRNA turnover and demonstrated its close connection with the process of translation. Peltz received his PhD at the McArdle Laboratory for Cancer Research at the University of Wisconsin.

William S. Sly, MD

Saint Louis University School of Medicine
email | web site | publications

William S. Sly is professor of pediatrics, biochemistry, and molecular biology at the Saint Louis University School of Medicine, where he chairs the department of biochemistry and molecular biology. Before coming to the university in 1984, he was professor of pediatrics, genetics, and internal medicine at the Washington University School of Medicine. From 1964 to 1975, he served as director for the division of medical genetics at the Washington University School of Medicine and Children's Hospital.

After receiving his MD degree from the Saint Louis University School of Medicine, Sly did his internship and residency at Barnes Hospital, Saint Louis. He completed five years of postdoctoral training, starting in the laboratory of E. R. Stadtman at the National Institutes of Health. Sly is the recipient of a number of awards and in 1989 was elected to the National Academy of Sciences. He has served on many NIH study sections, scientific review boards, and editorial boards and is the author of at least 291 peer-reviewed papers.

Alan E. Smith, PhD

Genzyme Corporation
email | publications

Alan E. Smith is senior vice president for research and chief scientific officer at Genzyme Corporation, where he has overall responsibility for the company's science. Before Genzyme acquired Integrated Genetics (IG) in 1989, he was vice president and scientific director at IG. Prior to joining IG in 1984, Smith was head of the biochemistry division of the National Institute for Medical Research and on the scientific staff of the Imperial Cancer Research Fund in London.

Smith received his PhD from the Laboratory of Molecular Biology, Cambridge, England. He has authored and co-authored over 180 publications in biochemistry, virology, molecular biology, and gene therapy.

H. Lee Sweeney, PhD

University of Pennsylvania School of Medicine
email | web site | publications

H. Lee Sweeney is chairman of the physiology department at the University of Pennsylvania School of Medicine. He has been a professor in the departments of medicine and surgery since 1998. From 1985 to 1989 he was assistant professor at the University of Texas at Austin.

Sweeney, who was named fellow of the American Heart Association in 2001, has played organizing roles in numerous scientific conferences, has been active on the editorial board of several scientific journals, and has served on national scientific committees, including the NASA Review Committee for Life Sciences. He received his PhD from Harvard University and completed his postdoctoral training at the University of Texas Southwestern Medical School.

Anjani Shah

Anjani Shah is a freelance science and medical writer based in New York City with a PhD in cell biology.