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November 1993, Vol 147, No. 11 >
Article | November 1993

Gene Therapy FREE

Fred Levine, MD, PhD; Theodore Friedmann, MD
[+] Author Affiliations

Accepted for publication June 21, 1993.

Reprint requests to Department of Pediatrics, Center for Molecular Genetics, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0634 (Dr Levine).


Am J Dis Child. 1993;147(11):1167-1174. doi:10.1001/archpedi.1993.02160350041006.
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Comments

Genetics is playing an increasingly important role in medicine. It has become clear that genetic factors are involved in virtually every disease that afflicts humanity. Although conventional pharmacologic therapy is effective for many diseases, the underlying genetic predispositions that lead to the diseases are not influenced by these therapies. In particular, with few exceptions, therapy is woefully inadequate for diseases that follow a simple mendelian pattern of inheritance and thus are caused primarily by a single genetic defect.

The ultimate goal of treatment of genetic disease is repair of the genetic defect, ie, gene therapy.1,2 In the past few years, there has been an explosion of interest in this new form of medical treatment. As gene therapy increasingly moves from research laboratories to clinical trials, it will inevitably become standard therapy for many diseases commonly seen by general pediatricians, such as cystic fibrosis (CF), hemophilia, and sickle cell anemia. Thus,

REFERENCES

1 +
Anderson WF.  Human gene therapy . Science . 1991;;256:808-813.
2 +
Mulligan RC.  The basic science of gene therapy . Science . 1993;;260: 926-931.
3 +
Friedmann T.  A brief history of gene therapy . Nat Genet . 1992;;2:93-98.
4 +
Szybalska EH, Szybalski W.  Genetics of human cells lines, IV: DNA-mediated heritable transformation of a biochemical trait . Proc Natl Acad Sci USA . 1962;;48:2026-2034.
5 +
Friedmann T, Roblin R.  Gene therapy for human genetic disease? Science . 1972;;178:648-649.
6 +
Roemer K, Johnson PA, Friedmann T.  Activity of the simian virus 40 early promoter-enhancer in herpes simplex virus type 1 vectors is dependent on its position, the infected cell type, and the presence of Vmwl75 . J Virol . 1991;;65:6900-6912.
7 +
McLachlin JR, Cornetta K, Eglitis MA, et al.  Retroviral-mediated gene transfer . Prog Nucleic Acid Res Mol Biol . 1990;;38:91-135.
8 +
Salmons B, Gunzburg WH.  Targeting of retroviral vectors for gene therapy . Hum Gene Ther . 1993;;4:129-141.
9 +
Berkner KL.  Expression of heterologous sequences in adenoviral vectors . Curr Top Microbiol Immunol . 1991;;158:39-66.
10 +
Jaffe HA, Danel C, Longnecker G, et al.  Adenovirus mediated in vivo gene transfer and expression in normal rat liver . Nature . 1992;;1:372-378.
11 +
Davidson BL, Allen ED, Kozarsky KF, et al.  A model system for in vivo gene transfer into the central nervous system using an adenoviral vector . Nature Genet . 993;3:219-223.
12 +
Akli S, Caillaud C, Vigne E, et al.  Transfer of a foreign gene into the grain using adenovirus vectors . Nature Genet . 1993;;3:224-228.
13 +
Bajocchi G, Feldman SH, Crystal RG, et al.  Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors . Nature Genet. 1993;;3:229-234.
14 +
Breakefield XO, DeLuca NA.  Herpes simplex virus for gene delivery to neurons . New Biol . 1991;;3:474-485.
15 +
Miyanohara A, Johnson PA, Elam RL, et al.  Direct gene transfer to the liver with herpes simplex virus type 1 vectors: transient production of physiologically relevant levels of circulating factor IX . New Biol . 1992;;4:238-246.
16 +
Johnson PA, Miyanohara A, Levine F, et al.  Cytotoxicity of a replication-defective mutant of herpes simplex virus type 1 .J Virol . 1992;;66: 2952-2965.
17 +
Muzyczka N.  Use of adeno-associated virus as a general transduction vector for mammalian cells . Curr Top Microbiol Immunol . 1991;;158:97-129.
18 +
Samulski RJ, Zhy X, Xiao XB, et al.  Targeted integration of adeno-associated virus (AAV) into human chromosome 19 . EMBO J . 1991;;10:3941-3950.
19 +
Wu GY, Wilson JM, Shalaby F, et al.  Receptor-mediated gene delivery in vivo: partial correction of genetic analbuminemia in Nagase rats . J Biol Chem . 1991;;266:14338-14342.
20 +
Zenke M, Steinlein P, Wagner E, et al.  Receptor-mediated endocytosis of transferrin polycation conjugates: an efficient way to introduce DNA into hematopoietic cells . Proc Natl Acad Sci U S A . 1990;;87:3655-3659.
21 +
Wolff JA, Malone RW, Williams P, et al.  Direct gene transfer into mouse muscle in vivo . Science . 1990;;247:1465-1468.
22 +
Lin H, Parmacek MS, Morle G, et al.  Expression of recombinant genes in myocardium in vivo after direct injection of DNA . Circulation . 1990;;82: 2217-2221.
23 +
Acsadi G, Dickson G, Love DR, et al.  Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs . Nature . 1991;352:815-818.
24 +
Cohen J.  Naked DNA points way to vaccines . Science . 1993;;259: 1691-1692.
25 +
Ulmer JB, Donnelly JJ, Parker SE, et al.  Heterologous protection against influenza by injection of DNA encoding a viral protein . Science . 1993;;259: 1745-1750.
26 +
Wang C-Y, Huang L.  pH-sensitive immunoliposomes mediate target-cell-specific delivery and controlled expression of a foreign gene in mouse . Proc Natl Acad Sci USA . 1987;;84:7851-7855.
27 +
Hyde SC, Gill DR, Higgins CF, et al.  Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy . Nature . 1993;;362:250-255.
28 +
Schuening FG.  Gene transfer into hematopoietic stem cells . Curr Top Microbiol Immunol . 1992;;177:237-245.
29 +
Van Beusechem VW, Kukler A, Heidt PJ, et al.  Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone-marrow cells . Proc Natl Acad Sci U S A . 1992;;89: 7640-7644.
30 +
Hedner U, Davie EW.  Introduction to hemostasis and the vitamin K-dependent coagulation factors . In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:2107-2134.
31 +
Armentano D, Thompson AR, Darlington G, et al.  Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: potential for gene therapy of hemophilia B . Proc Natl Acad Sci U S A . 1990;;87: 6141-6145.
32 +
St Louis D, Verma I.  An alternative approach to somatic cell gene therapy . Proc Natl Acad Sci U S A . 1988;;85:3150-3154.
33 +
Palmer TD, Rosman GJ, Osborne WRA, et al.  Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes . Proc Natl Acad Sci U S A . 1991;;88:1330-1334.
34 +
Yao Shou-N, Wilson JM, Nabel EG, et al.  Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B . Proc Natl Acad Sci U S A . 1991;;88:8101-8105.
35 +
Gerrard AJ, Hudson DL, Brownlee GG, et al.  Towards gene therapy for haemophilia B using primary human keratinocytes . Nature Genet . 1993;; 3:180-183.
36 +
Roman M, Axelrod JH, Dai Y, et al.  Circulating human or canine factor IX from retrovirally transduced primary myoblasts and established myoblast cell lines grafted into murine skeletal muscle . Somat Cell Mol Genet . 1992;;18:247-258.
37 +
Chowdhury JR, Grossman M, Gupta S, et al.  Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits . Science . 1991;;254:1802-1805.
38 +
Randall T.  First gene therapy for inherited hypercholesterolemia a partial success . JAMA . 1993;;269:837-838.
39 +
Ferry N, Duplessis O, Houssin D, et al.  Retroviral-mediated gene transfer into hepatocytes in vivo . Proc Natl Acad Sci U S A . 1991;;88:8377-8381.
40 +
Barr E, Leiden JM.  Systemic delivery of recombinant proteins by genetically modified myoblasts . Science . 1991;;254:1507-1509.
41 +
Dhawan J, Pan LC, Pavlath GK, et al.  Systemic delivery of human growth hormone by injection of genetically engineered myoblasts . Science . 1991;;254:1509-1512.
42 +
Rosenberg SA, Aebersold P, Cornetta K, et al.  Gene transfer into humans: immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction . N Engl J Med . 1990;;323:570-578.
43 +
Brenner MK, Rill DR, Moen RC, et al.  Gene-marking to trace origin of relapse after autologous bone-marrow transplantation . Lancet . 1993;;341:85-86.
44 +
Lemischka IR.  What we have learned from retroviral marking of hematopoietic stem cells . Curr Top Microbiol Immunol . 1992;;177:59-71.
45 +
Pardoll D.  Immunotherapy with cytokine gene-transduced tumor cells: the next wave in gene therapy for cancer . Curr Opin Oncol . 1992;;4: 1124-1129.
46 +
Gansbacher B, Zier K, Daniels B, et al.  Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity . J Exp Med . 1990;;172:1217-1224.
47 +
Golumbek PT, Lazenby AJ, Levitsky HI, et al.  Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4 . Science . 1991;;254:713-716.
48 +
Culver KW, Ram Z, Wallbridge S, et al.  In vivo gene transfer with retroviral vector producer cells for treatment of experimental brain tumors . Science . 1992;;256:1550-1552.
49 +
Trojan J, Blossey BK, Johnson TR, et al.  Loss of tumorigenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor I . Proc Natl Acad Sci U S A . 1992;;89:4874-4878.
50 +
Cheng J, Yee J-K, Yeargin J, et al.  Suppression of acute lymphoblastic leukemia by the human wild-type p53 gene . Cancer Res . 1992;;52:222-226.
51 +
Mastrangeli A, Rosenfeld DC, Stratford-Perricaudet L, et al.  Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer . J Clin Invest . 1993;;91:225-234.
52 +
Rosenfeld MA, Siegfried W, Yoshimura K, et al.  Adenovirus-mediated transfer of a recombinant 1-antitrypsin gene to the lung epithelium in vivo . Science . 1991;;252:431-434.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

References

1 +
Anderson WF.  Human gene therapy . Science . 1991;;256:808-813.
2 +
Mulligan RC.  The basic science of gene therapy . Science . 1993;;260: 926-931.
3 +
Friedmann T.  A brief history of gene therapy . Nat Genet . 1992;;2:93-98.
4 +
Szybalska EH, Szybalski W.  Genetics of human cells lines, IV: DNA-mediated heritable transformation of a biochemical trait . Proc Natl Acad Sci USA . 1962;;48:2026-2034.
5 +
Friedmann T, Roblin R.  Gene therapy for human genetic disease? Science . 1972;;178:648-649.
6 +
Roemer K, Johnson PA, Friedmann T.  Activity of the simian virus 40 early promoter-enhancer in herpes simplex virus type 1 vectors is dependent on its position, the infected cell type, and the presence of Vmwl75 . J Virol . 1991;;65:6900-6912.
7 +
McLachlin JR, Cornetta K, Eglitis MA, et al.  Retroviral-mediated gene transfer . Prog Nucleic Acid Res Mol Biol . 1990;;38:91-135.
8 +
Salmons B, Gunzburg WH.  Targeting of retroviral vectors for gene therapy . Hum Gene Ther . 1993;;4:129-141.
9 +
Berkner KL.  Expression of heterologous sequences in adenoviral vectors . Curr Top Microbiol Immunol . 1991;;158:39-66.
10 +
Jaffe HA, Danel C, Longnecker G, et al.  Adenovirus mediated in vivo gene transfer and expression in normal rat liver . Nature . 1992;;1:372-378.
11 +
Davidson BL, Allen ED, Kozarsky KF, et al.  A model system for in vivo gene transfer into the central nervous system using an adenoviral vector . Nature Genet . 993;3:219-223.
12 +
Akli S, Caillaud C, Vigne E, et al.  Transfer of a foreign gene into the grain using adenovirus vectors . Nature Genet . 1993;;3:224-228.
13 +
Bajocchi G, Feldman SH, Crystal RG, et al.  Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors . Nature Genet. 1993;;3:229-234.
14 +
Breakefield XO, DeLuca NA.  Herpes simplex virus for gene delivery to neurons . New Biol . 1991;;3:474-485.
15 +
Miyanohara A, Johnson PA, Elam RL, et al.  Direct gene transfer to the liver with herpes simplex virus type 1 vectors: transient production of physiologically relevant levels of circulating factor IX . New Biol . 1992;;4:238-246.
16 +
Johnson PA, Miyanohara A, Levine F, et al.  Cytotoxicity of a replication-defective mutant of herpes simplex virus type 1 .J Virol . 1992;;66: 2952-2965.
17 +
Muzyczka N.  Use of adeno-associated virus as a general transduction vector for mammalian cells . Curr Top Microbiol Immunol . 1991;;158:97-129.
18 +
Samulski RJ, Zhy X, Xiao XB, et al.  Targeted integration of adeno-associated virus (AAV) into human chromosome 19 . EMBO J . 1991;;10:3941-3950.
19 +
Wu GY, Wilson JM, Shalaby F, et al.  Receptor-mediated gene delivery in vivo: partial correction of genetic analbuminemia in Nagase rats . J Biol Chem . 1991;;266:14338-14342.
20 +
Zenke M, Steinlein P, Wagner E, et al.  Receptor-mediated endocytosis of transferrin polycation conjugates: an efficient way to introduce DNA into hematopoietic cells . Proc Natl Acad Sci U S A . 1990;;87:3655-3659.
21 +
Wolff JA, Malone RW, Williams P, et al.  Direct gene transfer into mouse muscle in vivo . Science . 1990;;247:1465-1468.
22 +
Lin H, Parmacek MS, Morle G, et al.  Expression of recombinant genes in myocardium in vivo after direct injection of DNA . Circulation . 1990;;82: 2217-2221.
23 +
Acsadi G, Dickson G, Love DR, et al.  Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs . Nature . 1991;352:815-818.
24 +
Cohen J.  Naked DNA points way to vaccines . Science . 1993;;259: 1691-1692.
25 +
Ulmer JB, Donnelly JJ, Parker SE, et al.  Heterologous protection against influenza by injection of DNA encoding a viral protein . Science . 1993;;259: 1745-1750.
26 +
Wang C-Y, Huang L.  pH-sensitive immunoliposomes mediate target-cell-specific delivery and controlled expression of a foreign gene in mouse . Proc Natl Acad Sci USA . 1987;;84:7851-7855.
27 +
Hyde SC, Gill DR, Higgins CF, et al.  Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy . Nature . 1993;;362:250-255.
28 +
Schuening FG.  Gene transfer into hematopoietic stem cells . Curr Top Microbiol Immunol . 1992;;177:237-245.
29 +
Van Beusechem VW, Kukler A, Heidt PJ, et al.  Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone-marrow cells . Proc Natl Acad Sci U S A . 1992;;89: 7640-7644.
30 +
Hedner U, Davie EW.  Introduction to hemostasis and the vitamin K-dependent coagulation factors . In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:2107-2134.
31 +
Armentano D, Thompson AR, Darlington G, et al.  Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: potential for gene therapy of hemophilia B . Proc Natl Acad Sci U S A . 1990;;87: 6141-6145.
32 +
St Louis D, Verma I.  An alternative approach to somatic cell gene therapy . Proc Natl Acad Sci U S A . 1988;;85:3150-3154.
33 +
Palmer TD, Rosman GJ, Osborne WRA, et al.  Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes . Proc Natl Acad Sci U S A . 1991;;88:1330-1334.
34 +
Yao Shou-N, Wilson JM, Nabel EG, et al.  Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B . Proc Natl Acad Sci U S A . 1991;;88:8101-8105.
35 +
Gerrard AJ, Hudson DL, Brownlee GG, et al.  Towards gene therapy for haemophilia B using primary human keratinocytes . Nature Genet . 1993;; 3:180-183.
36 +
Roman M, Axelrod JH, Dai Y, et al.  Circulating human or canine factor IX from retrovirally transduced primary myoblasts and established myoblast cell lines grafted into murine skeletal muscle . Somat Cell Mol Genet . 1992;;18:247-258.
37 +
Chowdhury JR, Grossman M, Gupta S, et al.  Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits . Science . 1991;;254:1802-1805.
38 +
Randall T.  First gene therapy for inherited hypercholesterolemia a partial success . JAMA . 1993;;269:837-838.
39 +
Ferry N, Duplessis O, Houssin D, et al.  Retroviral-mediated gene transfer into hepatocytes in vivo . Proc Natl Acad Sci U S A . 1991;;88:8377-8381.
40 +
Barr E, Leiden JM.  Systemic delivery of recombinant proteins by genetically modified myoblasts . Science . 1991;;254:1507-1509.
41 +
Dhawan J, Pan LC, Pavlath GK, et al.  Systemic delivery of human growth hormone by injection of genetically engineered myoblasts . Science . 1991;;254:1509-1512.
42 +
Rosenberg SA, Aebersold P, Cornetta K, et al.  Gene transfer into humans: immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction . N Engl J Med . 1990;;323:570-578.
43 +
Brenner MK, Rill DR, Moen RC, et al.  Gene-marking to trace origin of relapse after autologous bone-marrow transplantation . Lancet . 1993;;341:85-86.
44 +
Lemischka IR.  What we have learned from retroviral marking of hematopoietic stem cells . Curr Top Microbiol Immunol . 1992;;177:59-71.
45 +
Pardoll D.  Immunotherapy with cytokine gene-transduced tumor cells: the next wave in gene therapy for cancer . Curr Opin Oncol . 1992;;4: 1124-1129.
46 +
Gansbacher B, Zier K, Daniels B, et al.  Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity . J Exp Med . 1990;;172:1217-1224.
47 +
Golumbek PT, Lazenby AJ, Levitsky HI, et al.  Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4 . Science . 1991;;254:713-716.
48 +
Culver KW, Ram Z, Wallbridge S, et al.  In vivo gene transfer with retroviral vector producer cells for treatment of experimental brain tumors . Science . 1992;;256:1550-1552.
49 +
Trojan J, Blossey BK, Johnson TR, et al.  Loss of tumorigenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor I . Proc Natl Acad Sci U S A . 1992;;89:4874-4878.
50 +
Cheng J, Yee J-K, Yeargin J, et al.  Suppression of acute lymphoblastic leukemia by the human wild-type p53 gene . Cancer Res . 1992;;52:222-226.
51 +
Mastrangeli A, Rosenfeld DC, Stratford-Perricaudet L, et al.  Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer . J Clin Invest . 1993;;91:225-234.
52 +
Rosenfeld MA, Siegfried W, Yoshimura K, et al.  Adenovirus-mediated transfer of a recombinant 1-antitrypsin gene to the lung epithelium in vivo . Science . 1991;;252:431-434.

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