0
January 5, 1994, Vol 271, No. 1 >
ARTICLE | January 5, 1994

Gene Therapy and the Hemophilias FREE

Jay Nelson Lozier, MD, PhD; Kenneth M. Brinkhous, MD
[+] Author Affiliations

Reprint requests to University of North Carolina, Department of Medicine, CB# 7035, Chapel Hill, NC 27599 (Dr Lozier).


JAMA. 1994;271(1):47-51. doi:10.1001/jama.1994.03510250063036
Text Size: A A A
Published online
Article
References

Gene therapy for hemophilia A and B, now in the developmental stage, holds promise of a therapeutic revolution, resulting in amelioration or cure of the hemorrhagic diatheses. The genes for factor VIII and IX have been cloned, and vectors for the transfer of their cDNA into cells have been developed. Although viral and nonviral constructs containing the hemophilia gene have been used, most often modified retroviruses or adenoviruses have been employed. Cells that have been targeted for genetic modification to produce the antihemophilic proteins include hepatocytes, muscle cells, endothelial cells, keratinocytes, and fibroblasts. The delivery system may be (1) ex vivo, with implantation of modified cultured hemophilic cells in the donor, either in tissues or in semipermeable capsules, or (2) in vivo, the vector being delivered directly to target cells, genetically modifying them in situ. Successful in vivo therapy has been demonstrated in a hemophilic animal model, with conversion to a less severe hemophilic state.

(JAMA. 1994;271:47-51)

REFERENCES

1 +
Mandel JL, Willard HF, Nussbaum RL, Davies KE, Romeo G.  Report of the committee on the genetic constitution of the X chromosome. Cytogenet Cell Genet . 1988;;49:107-128.
2 +
Camerino G, Grzeschik KH, Jaye M, et al.  Regional localization on the human X chromosome and polymorphism of the coagulation factor IX gene (hemophilia B locus). Proc Natl Acad Sci U S A . 1984;;81:498-502.
3 +
Lozier JN, High KA.  Molecular basis of hemophilia. Hematol Pathol . 1990;;4:1-26.
4 +
Miller AD.  Progress toward human gene therapy. Blood . 1990;;76:271-278.
5 +
Thompson AR.  Status of gene transfer for hemophilia A and B. Thromb Haemost . 1991;;66:119-122.
6 +
Brinkhous KM.  Gene transfer in the hemophilias: retrospect and prospect. Thromb Res . 1992;;67: 329-338.
7 +
Roberts HR, Lozier JN.  New perspectives on the coagulation cascade. Hosp Pract . 1992;;27:97-112.
8 +
Levine PH, Brettler DB.  Clinical aspects and therapy for hemophilia A.  In: Hoffman R, Benz EJ, Shattil SJ, eds. Hematology, Basic Principles and Practice . New York, NY: Churchill Livingstone; 1991;:1290-1304.
9 +
Rees DJG, Rizza CR, Brownlee CG.  Haemophilia B caused by a point mutation in a donor splice junction of the human factor IX gene. Nature . 1985;; 316:643-645.
10 +
Goedert JJ, Kessler CM, Aledort LM, et al.  A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med . 1989;; 321:1141-1152.
11 +
Troisi CL, Hollinger FB, Hoots WK, et al.  A multicenter study of viral hepatitis in a United States hemophilic population. Blood . 1993;;81:412-418.
12 +
Schimpf K, Brackmann HH, Kreuz W, et al.  Absence of anti-human immunodeficiency virus types 1 and 2 seroconversion after the treatment of hemophilia A or von Willebrand's disease with pasteurized factor VIII concentrate. N Engl J Med . 1989;;321:1148-1152.
13 +
Schimpf K, Mannucci PM, Kreutz W, et al.  Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusions. N Engl J Med . 1987;;316:918-922.
14 +
White GC, Campbell WM, Kingdon HS, Shoemaker CB.  Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med . 1989;;320:166-170.
15 +
Lusher JM, Arkin S, Abildgaard CF, et al.  Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med . 1993;;328:453-459.
16 +
Schwartz RS, Abildgaard CF, Aledort LM, et al.  Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med . 1990;;323:1800-1805.
17 +
Macik BG, Hohneker J, Roberts HR, Griffin AM.  The use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor. Am J Hematol . 1989;;32:232-234.
18 +
Brinkhous KM, Hedner U, Garris JB, Diness V, Read MS.  Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia E, and von Willebrand disease. Proc Natl Acad Sci U S A . 1989;;86:1382-1386.
19 +
Verma IM.  Gene therapy. Sci Am . 1990;;63:68-84.
20 +
Miller AD.  Retrovirus packaging cells. Hum Gene Ther . 1990;;1:5-14.
21 +
Nichols EK. Human Gene Therapy . Cambridge, Mass: Harvard University Press; 1988;:120-121.
22 +
Zhu N, Liggitt D, Liu Y, Debs R.  Systemic gene expression after intravenous DNA delivery into adult mice. Science . 1993;;261:209-211.
23 +
Wolff JA, Malone RW, Williams P, et al.  Direct gene transfer into mouse muscle in vivo. Science . 1990;;247:1465-1468.
24 +
Quantin B, Perricaudet LD, Taybakhsh S, Mandel JL.  Adenovirus as an expression vector in muscle cells in vivo. Proc Natl Acad Sci U S A . 1992;;89: 2581-2584.
25 +
Yates JL, Warren N, Sugden B.  Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature . 1985;;313:812-815.
26 +
Lozier JN, Palmer TD, Thompson AR, Miller AD, Brinkhous KM, High KA.  Production of recombinant canine factor IX by hollow fiber tissue culture. Thromb Haemost . 1991;;65:1158.
27 +
St Louis D, Verma IM.  An alternative approach to somatic cell gene therapy. Proc Natl Acad Sci U S A . 1988;;85:3150-3154.
28 +
Palmer TD, Thompson AR, Miller AD.  Production of human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B. Blood . 1989;;73:438-445.
29 +
Carr-Brendel V, Lozier JN, Thomas TJ, et al.  An immunoisolation device for implantation of genetically engineered cells: long-term expression of factor IX in rats. J Cell Biochem . 1993;;17E:224.
30 +
Hoeben RC, van der Jagt RCM, Schoute F, et al.  Expression of functional factor VIII in primary human skin fibroblasts after retrovirus-mediated gene transfer. J Biol Chem . 1990;;265:7318-7323.
31 +
Hoeben RC, Fallaux FJ, Tilburg NHV, et al.  Toward gene therapy for hemophilia A: long-term persistence of factor VIII-secreting fibroblasts after transplantation into immunodeficient mice. Hum Gene Ther . 1993;;4:179-186.
32 +
Noe DA, Bell WR, Ness PM, Levin J.  Plasma clearance rates of coagulation factors VIII and IX in factor-deficient individuals. Blood . 1986;;67:969-972.
33 +
Kim HC, McMillan CW, White GC, Bergman GE, Horton MW, Saidi P.  Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates. Blood . 1992;;79:568-575.
34 +
Stern DM, Knitter G, Kisiel W, Nawroth PP.  In vivo evidence of intravascular binding sites for coagulation factor IX. Br J Haematol . 1987;;66:227-232.
35 +
Cheung WF, Hamaguchi N, Smith KJ, Stafford DW.  The binding of human factor IX to endothelial cells is mediated by residues 3-11. J Biol Chem . 1992;;267:20529-20531.
36 +
Wu GY, Wilson JM, Shalaby F, Grossman M, Shafritz DA, Wu CH.  Receptor-mediated gene delivery in vivo: partial correction of genetic analbuminemia in Nagase rats. J Biol Chem . 1991;;266: 14338-14342.
37 +
Salmons B, Gunzburg WH.  Targeting of retroviral vectors for gene therapy. Hum Gene Ther . 1993;;4:129-141.
38 +
Nabel EG, Plautz G, Nabel GJ.  Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science . 1990;;249:1285-1288.
39 +
Kay MA, Rothenberg S, Landen CN, et al.  In vivo therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science . 1993;; 262:117-119.
40 +
Cardoso JE, Branchereau S, Jeyaraj PR, Houssin D, Danos O, Heard JM.  In situ retrovirus-mediated gene transfer into dog liver. Hum Gene Ther . 1993;;4:411-418.
41 +
Lozier JN, Thompson AR, Hu P-C, et al.  Efficient transfection of canine primary cells in a hemophilia B model. Hum Gene Ther . In press.
42 +
Gao I, Wagner E, Cotten M, et al.  Direct in vivo gene transfer to airway epithelium employing adenovirus-polylysine-DNA complexes. Hum Gene Ther . 1993;;4:17-24.
43 +
Neel JV.  Germ line gene therapy: another view. Hum Gene Ther . 1993;;4:127-128.
44 +
Cornetta K, Morgan RA, Anderson WF.  Safety issues related to retroviral-mediated gene transfer in humans. Hum Gene Ther . 1991;;2:5-14.
45 +
Wood WI, Cappon DJ, Simonsen CC, et al.  Expression of active human factor VIII from recombinant DNA clones. Nature . 1984;;312:330-337.
46 +
Kaufman RJ, Wasley LC, Davies MV, Wise RJ, Israel DI, Dorner AJ.  Effect of von Willebrand factor coexpression on the synthesis and secretion of factor VIII in Chinese hamster ovary cells. Mol Cell Biol . 1989;;9:1233-1242.
47 +
Israel DI, Kaufman RJ.  Retroviral-mediated transfer and amplification of a functional human factor VIII gene. Blood . 1990;;75:1074-1080.
48 +
Sandberg H, Lind P, Spira J.  Characteristics of a new recombinant factor VIII derivative. Thromb Haemost . 1991;;65:942.
49 +
Brinkhous KM, Widlund L, Read MS.  Pharmacokinetics and pharmacodynamics of a B-domain deleted recombinant factor VIII derivative r-VIII SO, in canine hemophilia. Thromb Haemost . 1993;; 69:852.
50 +
Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC, Kaufman RJ.  A large region (≈95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA . 1986;; 83:5939-5942.
51 +
Axelrod JH, Read MS, Brinkhous KM, Verma IM.  Phenotypic correction of factor IX deficiency in skin fibroblasts of hemophilic dogs. Proc Natl Acad Sci US A . 1990;;87:5173-5177.
52 +
Gerrard AJ, Hudson DI, Brownlee GG, Watt FM.  Towards gene therapy for haemophilia B using primary human keratinocytes. Nature Genetics . 1993;;3:180-183.
53 +
Yao SN, Wilson JM, Nabel EG, Kurachi S, Hachiya HL, Kurachi K.  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.
54 +
Yao SN, Kurachi K.  Expression of human factor IX in mice after injection of genetically modified myoblasts. Proc Natl Acad Sci U S A . 1992;;89: 3357-3361.
55 +
Armentano D, Thompson AR, Darlington G, Woo SLC.  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.
56 +
Busby S, Kumar A, Joseph M, et al.  Expression of active human factor IX in transfected cells. Nature . 1985;;316:271-273.
57 +
Kaufman RJ, Wasley LC, Furie BC, Furie B, Shoemaker CB.  Expression, purification, and characterization of recombinant gamma-carboxylated factor IX synthesized in Chinese hamster ovary cells. J Biol Chem . 1986;;261:9622-9628.
58 +
Dai Y, Roman M, Naviaux RK, Verma IM.  Gene therapy via primary myoblasts: long-term expression of factor IX protein following transplantation in vivo. Proc Natl Acad Sci U S A . 1992;;89:10892-10895.
59 +
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.
60 +
Anson DS, Austen DEG, Brownlee GG.  Expression of active human clotting factor IX from recombinant DNA clones in mammalian cells. Nature . 1985;;315:683-685.
61 +
De La Salle H, Altenburger W, Elkaim R, et al.  Active gamma-carboxylated human factor IX expressed using recombinant DNA techniques. Nature . 1985;;316:268-270.
62 +
Ramesh N, Lau S, Palmer TD, Storb R, Osborne WRA.  High level human adenosine deaminase expression in dog skin fibroblasts is not sustained following transplantation. Hum Gene Ther . 1993;;4:3-7.
63 +
Smith TAG, Mehaffey MG, Kayda DB, et al.  Adenovirus-mediated expression of therapeutic plasma levels of human factor IX in mice. Nat Genet . 1993;;5:397-402.
64 +
Kay MA, Landen CN, Rothenberg SR, et al.  In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc Natl Acad Sci U S A . In press.
65 +
Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA.  Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci U S A . 1989;;86:10095-10096.
66 +
Webster WP, Zukoski CF, Hutchin P, Reddick RL, Mandel SR, Penick GD.  Plasma factor VIII synthesis and control as revealed by canine organ transplantation. Am Physiol . 1971;;220:1147-1153.
67 +
Lewis JH, Bontempo FA, Spero JA, Ragni MV, Starzl TE.  Liver transplantation in a hemophiliac. N Engl J Med . 1985;;312:1189-1190.

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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

1 +
Mandel JL, Willard HF, Nussbaum RL, Davies KE, Romeo G.  Report of the committee on the genetic constitution of the X chromosome. Cytogenet Cell Genet . 1988;;49:107-128.
2 +
Camerino G, Grzeschik KH, Jaye M, et al.  Regional localization on the human X chromosome and polymorphism of the coagulation factor IX gene (hemophilia B locus). Proc Natl Acad Sci U S A . 1984;;81:498-502.
3 +
Lozier JN, High KA.  Molecular basis of hemophilia. Hematol Pathol . 1990;;4:1-26.
4 +
Miller AD.  Progress toward human gene therapy. Blood . 1990;;76:271-278.
5 +
Thompson AR.  Status of gene transfer for hemophilia A and B. Thromb Haemost . 1991;;66:119-122.
6 +
Brinkhous KM.  Gene transfer in the hemophilias: retrospect and prospect. Thromb Res . 1992;;67: 329-338.
7 +
Roberts HR, Lozier JN.  New perspectives on the coagulation cascade. Hosp Pract . 1992;;27:97-112.
8 +
Levine PH, Brettler DB.  Clinical aspects and therapy for hemophilia A.  In: Hoffman R, Benz EJ, Shattil SJ, eds. Hematology, Basic Principles and Practice . New York, NY: Churchill Livingstone; 1991;:1290-1304.
9 +
Rees DJG, Rizza CR, Brownlee CG.  Haemophilia B caused by a point mutation in a donor splice junction of the human factor IX gene. Nature . 1985;; 316:643-645.
10 +
Goedert JJ, Kessler CM, Aledort LM, et al.  A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med . 1989;; 321:1141-1152.
11 +
Troisi CL, Hollinger FB, Hoots WK, et al.  A multicenter study of viral hepatitis in a United States hemophilic population. Blood . 1993;;81:412-418.
12 +
Schimpf K, Brackmann HH, Kreuz W, et al.  Absence of anti-human immunodeficiency virus types 1 and 2 seroconversion after the treatment of hemophilia A or von Willebrand's disease with pasteurized factor VIII concentrate. N Engl J Med . 1989;;321:1148-1152.
13 +
Schimpf K, Mannucci PM, Kreutz W, et al.  Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusions. N Engl J Med . 1987;;316:918-922.
14 +
White GC, Campbell WM, Kingdon HS, Shoemaker CB.  Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med . 1989;;320:166-170.
15 +
Lusher JM, Arkin S, Abildgaard CF, et al.  Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med . 1993;;328:453-459.
16 +
Schwartz RS, Abildgaard CF, Aledort LM, et al.  Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med . 1990;;323:1800-1805.
17 +
Macik BG, Hohneker J, Roberts HR, Griffin AM.  The use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor. Am J Hematol . 1989;;32:232-234.
18 +
Brinkhous KM, Hedner U, Garris JB, Diness V, Read MS.  Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia E, and von Willebrand disease. Proc Natl Acad Sci U S A . 1989;;86:1382-1386.
19 +
Verma IM.  Gene therapy. Sci Am . 1990;;63:68-84.
20 +
Miller AD.  Retrovirus packaging cells. Hum Gene Ther . 1990;;1:5-14.
21 +
Nichols EK. Human Gene Therapy . Cambridge, Mass: Harvard University Press; 1988;:120-121.
22 +
Zhu N, Liggitt D, Liu Y, Debs R.  Systemic gene expression after intravenous DNA delivery into adult mice. Science . 1993;;261:209-211.
23 +
Wolff JA, Malone RW, Williams P, et al.  Direct gene transfer into mouse muscle in vivo. Science . 1990;;247:1465-1468.
24 +
Quantin B, Perricaudet LD, Taybakhsh S, Mandel JL.  Adenovirus as an expression vector in muscle cells in vivo. Proc Natl Acad Sci U S A . 1992;;89: 2581-2584.
25 +
Yates JL, Warren N, Sugden B.  Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature . 1985;;313:812-815.
26 +
Lozier JN, Palmer TD, Thompson AR, Miller AD, Brinkhous KM, High KA.  Production of recombinant canine factor IX by hollow fiber tissue culture. Thromb Haemost . 1991;;65:1158.
27 +
St Louis D, Verma IM.  An alternative approach to somatic cell gene therapy. Proc Natl Acad Sci U S A . 1988;;85:3150-3154.
28 +
Palmer TD, Thompson AR, Miller AD.  Production of human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B. Blood . 1989;;73:438-445.
29 +
Carr-Brendel V, Lozier JN, Thomas TJ, et al.  An immunoisolation device for implantation of genetically engineered cells: long-term expression of factor IX in rats. J Cell Biochem . 1993;;17E:224.
30 +
Hoeben RC, van der Jagt RCM, Schoute F, et al.  Expression of functional factor VIII in primary human skin fibroblasts after retrovirus-mediated gene transfer. J Biol Chem . 1990;;265:7318-7323.
31 +
Hoeben RC, Fallaux FJ, Tilburg NHV, et al.  Toward gene therapy for hemophilia A: long-term persistence of factor VIII-secreting fibroblasts after transplantation into immunodeficient mice. Hum Gene Ther . 1993;;4:179-186.
32 +
Noe DA, Bell WR, Ness PM, Levin J.  Plasma clearance rates of coagulation factors VIII and IX in factor-deficient individuals. Blood . 1986;;67:969-972.
33 +
Kim HC, McMillan CW, White GC, Bergman GE, Horton MW, Saidi P.  Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates. Blood . 1992;;79:568-575.
34 +
Stern DM, Knitter G, Kisiel W, Nawroth PP.  In vivo evidence of intravascular binding sites for coagulation factor IX. Br J Haematol . 1987;;66:227-232.
35 +
Cheung WF, Hamaguchi N, Smith KJ, Stafford DW.  The binding of human factor IX to endothelial cells is mediated by residues 3-11. J Biol Chem . 1992;;267:20529-20531.
36 +
Wu GY, Wilson JM, Shalaby F, Grossman M, Shafritz DA, Wu CH.  Receptor-mediated gene delivery in vivo: partial correction of genetic analbuminemia in Nagase rats. J Biol Chem . 1991;;266: 14338-14342.
37 +
Salmons B, Gunzburg WH.  Targeting of retroviral vectors for gene therapy. Hum Gene Ther . 1993;;4:129-141.
38 +
Nabel EG, Plautz G, Nabel GJ.  Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science . 1990;;249:1285-1288.
39 +
Kay MA, Rothenberg S, Landen CN, et al.  In vivo therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science . 1993;; 262:117-119.
40 +
Cardoso JE, Branchereau S, Jeyaraj PR, Houssin D, Danos O, Heard JM.  In situ retrovirus-mediated gene transfer into dog liver. Hum Gene Ther . 1993;;4:411-418.
41 +
Lozier JN, Thompson AR, Hu P-C, et al.  Efficient transfection of canine primary cells in a hemophilia B model. Hum Gene Ther . In press.
42 +
Gao I, Wagner E, Cotten M, et al.  Direct in vivo gene transfer to airway epithelium employing adenovirus-polylysine-DNA complexes. Hum Gene Ther . 1993;;4:17-24.
43 +
Neel JV.  Germ line gene therapy: another view. Hum Gene Ther . 1993;;4:127-128.
44 +
Cornetta K, Morgan RA, Anderson WF.  Safety issues related to retroviral-mediated gene transfer in humans. Hum Gene Ther . 1991;;2:5-14.
45 +
Wood WI, Cappon DJ, Simonsen CC, et al.  Expression of active human factor VIII from recombinant DNA clones. Nature . 1984;;312:330-337.
46 +
Kaufman RJ, Wasley LC, Davies MV, Wise RJ, Israel DI, Dorner AJ.  Effect of von Willebrand factor coexpression on the synthesis and secretion of factor VIII in Chinese hamster ovary cells. Mol Cell Biol . 1989;;9:1233-1242.
47 +
Israel DI, Kaufman RJ.  Retroviral-mediated transfer and amplification of a functional human factor VIII gene. Blood . 1990;;75:1074-1080.
48 +
Sandberg H, Lind P, Spira J.  Characteristics of a new recombinant factor VIII derivative. Thromb Haemost . 1991;;65:942.
49 +
Brinkhous KM, Widlund L, Read MS.  Pharmacokinetics and pharmacodynamics of a B-domain deleted recombinant factor VIII derivative r-VIII SO, in canine hemophilia. Thromb Haemost . 1993;; 69:852.
50 +
Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC, Kaufman RJ.  A large region (≈95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA . 1986;; 83:5939-5942.
51 +
Axelrod JH, Read MS, Brinkhous KM, Verma IM.  Phenotypic correction of factor IX deficiency in skin fibroblasts of hemophilic dogs. Proc Natl Acad Sci US A . 1990;;87:5173-5177.
52 +
Gerrard AJ, Hudson DI, Brownlee GG, Watt FM.  Towards gene therapy for haemophilia B using primary human keratinocytes. Nature Genetics . 1993;;3:180-183.
53 +
Yao SN, Wilson JM, Nabel EG, Kurachi S, Hachiya HL, Kurachi K.  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.
54 +
Yao SN, Kurachi K.  Expression of human factor IX in mice after injection of genetically modified myoblasts. Proc Natl Acad Sci U S A . 1992;;89: 3357-3361.
55 +
Armentano D, Thompson AR, Darlington G, Woo SLC.  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.
56 +
Busby S, Kumar A, Joseph M, et al.  Expression of active human factor IX in transfected cells. Nature . 1985;;316:271-273.
57 +
Kaufman RJ, Wasley LC, Furie BC, Furie B, Shoemaker CB.  Expression, purification, and characterization of recombinant gamma-carboxylated factor IX synthesized in Chinese hamster ovary cells. J Biol Chem . 1986;;261:9622-9628.
58 +
Dai Y, Roman M, Naviaux RK, Verma IM.  Gene therapy via primary myoblasts: long-term expression of factor IX protein following transplantation in vivo. Proc Natl Acad Sci U S A . 1992;;89:10892-10895.
59 +
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.
60 +
Anson DS, Austen DEG, Brownlee GG.  Expression of active human clotting factor IX from recombinant DNA clones in mammalian cells. Nature . 1985;;315:683-685.
61 +
De La Salle H, Altenburger W, Elkaim R, et al.  Active gamma-carboxylated human factor IX expressed using recombinant DNA techniques. Nature . 1985;;316:268-270.
62 +
Ramesh N, Lau S, Palmer TD, Storb R, Osborne WRA.  High level human adenosine deaminase expression in dog skin fibroblasts is not sustained following transplantation. Hum Gene Ther . 1993;;4:3-7.
63 +
Smith TAG, Mehaffey MG, Kayda DB, et al.  Adenovirus-mediated expression of therapeutic plasma levels of human factor IX in mice. Nat Genet . 1993;;5:397-402.
64 +
Kay MA, Landen CN, Rothenberg SR, et al.  In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc Natl Acad Sci U S A . In press.
65 +
Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA.  Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci U S A . 1989;;86:10095-10096.
66 +
Webster WP, Zukoski CF, Hutchin P, Reddick RL, Mandel SR, Penick GD.  Plasma factor VIII synthesis and control as revealed by canine organ transplantation. Am Physiol . 1971;;220:1147-1153.
67 +
Lewis JH, Bontempo FA, Spero JA, Ragni MV, Starzl TE.  Liver transplantation in a hemophiliac. N Engl J Med . 1985;;312:1189-1190.

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NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
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