Autoimmune anemia in macaques following erythropoietin gene therapy

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3303-3304 ◽  
Author(s):  
Pierre Chenuaud ◽  
Thibaut Larcher ◽  
Joseph E. Rabinowitz ◽  
Nathalie Provost ◽  
Yan Cherel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Therapy ◽  
Autoimmune Disease ◽  
Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Endogenous Erythropoietin ◽  
Cynomolgus Macaques ◽  
Vector Sequences ◽  
Gene Expressing ◽  
Self Antigen

Abstract We delivered the homologous erythropoietin (Epo) cDNA driven from a doxycycline-regulated promoter via recombinant adeno-associated virus in skeletal muscle of 9 cynomolgus macaques. Upon induction, rapid supraphysiologic levels of Epo were obtained. Unexpectedly, some individuals developed a profound anemia that correlated with the appearance of neutralizing antibodies against the endogenous Epo. Both the endogenous erythropoietin and vector sequences were identical. This is the first example of the inadvertent development of an autoimmune disease in primates as a result of gene transfer of a gene expressing a self-antigen. It raises some concerns when a therapeutic protein is produced at high levels from an ectopic site. (Blood. 2004;103:3303-3304)

Adeno-associated virus as a gene therapy vector: strategies to neutralize the neutralizing antibodies

2019 ◽  
Vol 19 (3) ◽  
pp. 289-298 ◽  
Author(s):  
Majid Lotfinia ◽  
Meghdad Abdollahpour-Alitappeh ◽  
Behzad Hatami ◽  
Mohammad Reza Zali ◽  
Morteza Karimipoor
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector

scholarly journals Preexisting Neutralizing Antibodies to Adeno-Associated Virus Capsids in Large Animals Other Than Monkeys May Confound In Vivo Gene Therapy Studies

2015 ◽  
Vol 26 (3) ◽  
pp. 103-105 ◽  
Author(s):  
Roberto Calcedo ◽  
Judith Franco ◽  
Qiuyue Qin ◽  
Dean W. Richardson ◽  
Jeffery B. Mason ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Virus Capsids ◽  
Large Animals ◽  
Therapy Studies

scholarly journals Relationship Between Neutralizing Antibodies Against Adeno-Associated Virus in the Vitreous and Serum: Effects on Retinal Gene Therapy

2019 ◽  
Vol 8 (2) ◽  
pp. 14 ◽  
Author(s):  
Suhwan Lee ◽  
Im Kyeung Kang ◽  
Ji Hyun Kim ◽  
Bok Kyoung Jung ◽  
Keerang Park ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Retinal Gene Therapy

scholarly journals High-Level Transgene Expression in Nonhuman Primate Liver with Novel Adeno-Associated Virus Serotypes Containing Self-Complementary Genomes

2006 ◽  
Vol 80 (12) ◽  
pp. 6192-6194 ◽  
Author(s):  
Guang-Ping Gao ◽  
You Lu ◽  
Xun Sun ◽  
Julie Johnston ◽  
Roberto Calcedo ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Nonhuman Primate ◽  
Transgene Expression ◽  
Second Generation ◽  
The Novel ◽  
Adeno Associated Virus ◽  
Cynomolgus Macaques ◽  
High Level

ABSTRACT Adeno-associated virus (AAV) vectors are being considered for in vivo applications of gene therapy in the treatment of a variety of disorders. This study evaluates the biology of second-generation vectors based on the novel serotypes AAV7 and AAV8 and containing self-complementary genomes in the nonhuman primate liver. Stable levels of transgene expression were achieved in cynomolgus macaques and suggest efficiencies at least 2 log higher than what could be achieved with AAV2 vectors using traditional single-stranded genomes. Analysis of DNAs from tissues revealed high levels of vector in the liver that appeared proportional to the relative amounts of transgene expression.

scholarly journals Epitope Mapping of Human Anti-Adeno-Associated Virus Type 2 Neutralizing Antibodies: Implications for Gene Therapy and Virus Structure

2000 ◽  
Vol 74 (4) ◽  
pp. 1761-1766 ◽  
Author(s):  
Marina Moskalenko ◽  
Lili Chen ◽  
Melinda van Roey ◽  
Brian A. Donahue ◽  
Richard O. Snyder ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Antibody Response ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Factor Ix ◽  
Enzyme Linked Immunosorbent Assay ◽  
Adeno Associated Virus ◽  
Human Factor Ix

ABSTRACT Recombinant adeno-associated virus type 2 (AAV) is a common vector used in human gene therapy protocols. We characterized the humoral immune response to AAV and observed that 80% of normal human subjects have anti-AAV antibodies and that 18% have neutralizing antibodies. To analyze the effect of neutralizing antibodies on AAV readministration, we attempted to deliver recombinant AAV expressing human factor IX (AAV-hFIX) intraportally into the livers of mice which had been preexposed to AAV and shown to harbor a neutralizing antibody response. While all naive control mice expressed hFIX following administration of AAV-hFIX, none of the mice with preexisting immunity expressed hFIX, even after transient immunosuppression at the time of the second administration with anti-CD4 or anti-CD40L antibodies. This suggests that preexisting immunity to AAV, as measured by a neutralizing antibody response, may limit AAV-mediated gene delivery. Using human sera in an enzyme-linked immunosorbent assay for AAV and a capsid peptide scan library to block antibody binding, we mapped seven regions of the AAV capsid containing immunogenic epitopes. Using pools of these peptides to inhibit the binding of neutralizing antibodies, we have identified a subset of six peptides which potentially reconstitute a single neutralizing epitope. This information may allow the design of reverse genetic approaches to circumvent the preexisting immunity that can be encountered in some individuals.

Prevalence of Neutralizing Antibodies Against Adeno-Associated Virus (AAV) Types 2, 5, and 6 in Cystic Fibrosis and Normal Populations: Implications for Gene Therapy Using AAV Vectors

2006 ◽  
Vol 0 (0) ◽  
pp. 060307123505001 ◽  
Author(s):  
Christine L. Halbert ◽  
A. Dusty Miller ◽  
Sharon McNamara ◽  
Julia Emerson ◽  
Ronald L. Gibson ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Normal Populations

scholarly journals Adeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions Upon Cell Entry

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1336
Author(s):  
Edward E. Large ◽  
Mark A. Silveria ◽  
Grant M. Zane ◽  
Onellah Weerakoon ◽  
Michael S. Chapman
Keyword(s):  
Gene Therapy ◽  
Molecular Interactions ◽  
Neutralizing Antibodies ◽  
Major Gene ◽  
Cell Entry ◽  
Transduction Efficiency ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Gene Therapy Vectors ◽  
Factor Interactions

Human gene therapy has advanced from twentieth-century conception to twenty-first-century reality. The recombinant Adeno-Associated Virus (rAAV) is a major gene therapy vector. Research continues to improve rAAV safety and efficacy using a variety of AAV capsid modification strategies. Significant factors influencing rAAV transduction efficiency include neutralizing antibodies, attachment factor interactions and receptor binding. Advances in understanding the molecular interactions during rAAV cell entry combined with improved capsid modulation strategies will help guide the design and engineering of safer and more efficient rAAV gene therapy vectors.

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