Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A

Gouri Shankar Pandey, Chen Yanover, Lisa M. Miller-Jenkins, Susan Garfield, Shelley A. Cole, Joanne E. Curran, Eric K. Moses, Natalia Rydz, Vijaya Simhadri, Chava Kimchi-Sarfaty, David Lillicrap, Kevin R. Viel, Teresa M. Przytycka, Glenn F. Pierce, Tom E. Howard*, Zuben E. Sauna, Jeanne Lusher, Meera Chitlur, Afshin Ameri, Kavita Natarajan & 31 others Rathi V. Iyer, Alexis A. Thompson, Raymond G. Watts, Christine L. Kempton, Craig Kessler, John C. Barrett, Erica J. Martin, Nigel Key, Rebecca Kruse-Jarres, Cindy Lessinger, Kathleen P. Pratt, Neil Josephson, Kevin McRedmond, Janice Withycombe, Christopher Walsh, Dana Matthews, Johnny Mahlangu, Amanda Krause, Rosemary Schwyzer, Rajendra Thejpal, Nadine Rapiti, Yasmin Goga, Marius Coetzee, David Stones, Kenneth Mann, Saulius Butenas, Laura Almasy, John Blangero, Mel Carless, Rajalingam Raja, Elaine Reed

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.

Original languageEnglish (US)
Pages (from-to)1318-1324
Number of pages7
JournalNature Medicine
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2013

Fingerprint

Factor VIII
Hemophilia A
Introns
Plasmas
T-Lymphocyte Epitopes
Biopsy
Pharmacogenetics
Gene Deletion
Missense Mutation
Therapeutics
Neutralizing Antibodies
Major Histocompatibility Complex
Liver
Mental Competency
Epitopes
Proteins
Genes
Messenger RNA
Defects
Molecules

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pandey, G. S., Yanover, C., Miller-Jenkins, L. M., Garfield, S., Cole, S. A., Curran, J. E., ... Reed, E. (2013). Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A. Nature Medicine, 19(10), 1318-1324. https://doi.org/10.1038/nm.3270
Pandey, Gouri Shankar ; Yanover, Chen ; Miller-Jenkins, Lisa M. ; Garfield, Susan ; Cole, Shelley A. ; Curran, Joanne E. ; Moses, Eric K. ; Rydz, Natalia ; Simhadri, Vijaya ; Kimchi-Sarfaty, Chava ; Lillicrap, David ; Viel, Kevin R. ; Przytycka, Teresa M. ; Pierce, Glenn F. ; Howard, Tom E. ; Sauna, Zuben E. ; Lusher, Jeanne ; Chitlur, Meera ; Ameri, Afshin ; Natarajan, Kavita ; Iyer, Rathi V. ; Thompson, Alexis A. ; Watts, Raymond G. ; Kempton, Christine L. ; Kessler, Craig ; Barrett, John C. ; Martin, Erica J. ; Key, Nigel ; Kruse-Jarres, Rebecca ; Lessinger, Cindy ; Pratt, Kathleen P. ; Josephson, Neil ; McRedmond, Kevin ; Withycombe, Janice ; Walsh, Christopher ; Matthews, Dana ; Mahlangu, Johnny ; Krause, Amanda ; Schwyzer, Rosemary ; Thejpal, Rajendra ; Rapiti, Nadine ; Goga, Yasmin ; Coetzee, Marius ; Stones, David ; Mann, Kenneth ; Butenas, Saulius ; Almasy, Laura ; Blangero, John ; Carless, Mel ; Raja, Rajalingam ; Reed, Elaine. / Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A. In: Nature Medicine. 2013 ; Vol. 19, No. 10. pp. 1318-1324.
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Pandey, GS, Yanover, C, Miller-Jenkins, LM, Garfield, S, Cole, SA, Curran, JE, Moses, EK, Rydz, N, Simhadri, V, Kimchi-Sarfaty, C, Lillicrap, D, Viel, KR, Przytycka, TM, Pierce, GF, Howard, TE, Sauna, ZE, Lusher, J, Chitlur, M, Ameri, A, Natarajan, K, Iyer, RV, Thompson, AA, Watts, RG, Kempton, CL, Kessler, C, Barrett, JC, Martin, EJ, Key, N, Kruse-Jarres, R, Lessinger, C, Pratt, KP, Josephson, N, McRedmond, K, Withycombe, J, Walsh, C, Matthews, D, Mahlangu, J, Krause, A, Schwyzer, R, Thejpal, R, Rapiti, N, Goga, Y, Coetzee, M, Stones, D, Mann, K, Butenas, S, Almasy, L, Blangero, J, Carless, M, Raja, R & Reed, E 2013, 'Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A', Nature Medicine, vol. 19, no. 10, pp. 1318-1324. https://doi.org/10.1038/nm.3270

Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A. / Pandey, Gouri Shankar; Yanover, Chen; Miller-Jenkins, Lisa M.; Garfield, Susan; Cole, Shelley A.; Curran, Joanne E.; Moses, Eric K.; Rydz, Natalia; Simhadri, Vijaya; Kimchi-Sarfaty, Chava; Lillicrap, David; Viel, Kevin R.; Przytycka, Teresa M.; Pierce, Glenn F.; Howard, Tom E.; Sauna, Zuben E.; Lusher, Jeanne; Chitlur, Meera; Ameri, Afshin; Natarajan, Kavita; Iyer, Rathi V.; Thompson, Alexis A.; Watts, Raymond G.; Kempton, Christine L.; Kessler, Craig; Barrett, John C.; Martin, Erica J.; Key, Nigel; Kruse-Jarres, Rebecca; Lessinger, Cindy; Pratt, Kathleen P.; Josephson, Neil; McRedmond, Kevin; Withycombe, Janice; Walsh, Christopher; Matthews, Dana; Mahlangu, Johnny; Krause, Amanda; Schwyzer, Rosemary; Thejpal, Rajendra; Rapiti, Nadine; Goga, Yasmin; Coetzee, Marius; Stones, David; Mann, Kenneth; Butenas, Saulius; Almasy, Laura; Blangero, John; Carless, Mel; Raja, Rajalingam; Reed, Elaine.

In: Nature Medicine, Vol. 19, No. 10, 01.10.2013, p. 1318-1324.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A

AU - Pandey, Gouri Shankar

AU - Yanover, Chen

AU - Miller-Jenkins, Lisa M.

AU - Garfield, Susan

AU - Cole, Shelley A.

AU - Curran, Joanne E.

AU - Moses, Eric K.

AU - Rydz, Natalia

AU - Simhadri, Vijaya

AU - Kimchi-Sarfaty, Chava

AU - Lillicrap, David

AU - Viel, Kevin R.

AU - Przytycka, Teresa M.

AU - Pierce, Glenn F.

AU - Howard, Tom E.

AU - Sauna, Zuben E.

AU - Lusher, Jeanne

AU - Chitlur, Meera

AU - Ameri, Afshin

AU - Natarajan, Kavita

AU - Iyer, Rathi V.

AU - Thompson, Alexis A.

AU - Watts, Raymond G.

AU - Kempton, Christine L.

AU - Kessler, Craig

AU - Barrett, John C.

AU - Martin, Erica J.

AU - Key, Nigel

AU - Kruse-Jarres, Rebecca

AU - Lessinger, Cindy

AU - Pratt, Kathleen P.

AU - Josephson, Neil

AU - McRedmond, Kevin

AU - Withycombe, Janice

AU - Walsh, Christopher

AU - Matthews, Dana

AU - Mahlangu, Johnny

AU - Krause, Amanda

AU - Schwyzer, Rosemary

AU - Thejpal, Rajendra

AU - Rapiti, Nadine

AU - Goga, Yasmin

AU - Coetzee, Marius

AU - Stones, David

AU - Mann, Kenneth

AU - Butenas, Saulius

AU - Almasy, Laura

AU - Blangero, John

AU - Carless, Mel

AU - Raja, Rajalingam

AU - Reed, Elaine

PY - 2013/10/1

Y1 - 2013/10/1

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