Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa

Su M. Lwin; Farhatullah Syed; Wei-li Di; Tendai Kadiyirire; Lu Liu; Alyson Guy; Anastasia Petrova; Alya Abdul-Wahab; Fiona Reid; Rachel Phillips; Maria Elstad; Christos Georgiadis; Sophia Aristodemou; Patricia A. Lovell; James R. Mcmillan; John Mee; Snaigune Miskinyte; Matthias Titeux; Linda Ozoemena; Rashida Pramanik; Sonia Serrano; Racheal Rowles; Clarisse Maurin; Elizabeth Orrin; Magdalena Martinez-Queipo; Ellie Rashidghamat; Christos Tziotzios; Alexandros Onoufriadis; Mei Chen; Lucas Chan; Farzin Farzaneh; Marcela Del Rio; Jakub Tolar; Johann W. Bauer; Fernando Larcher; Michael N. Antoniou; Alain Hovnanian; Adrian J. Thrasher; Jemima E. Mellerio; Waseem Qasim; John A. Mcgrath

doi:10.1172/jci.insight.126243

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa

Su M. Lwin, Farhatullah Syed, Wei-li Di, Tendai Kadiyirire, Lu Liu, Alyson Guy, Anastasia Petrova, Alya Abdul-Wahab, Fiona Reid, Rachel Phillips, Maria Elstad, Christos Georgiadis, Sophia Aristodemou, Patricia A. Lovell, James R. Mcmillan, John Mee, Snaigune Miskinyte, Matthias Titeux, Linda Ozoemena, Rashida PramanikSonia Serrano, Racheal Rowles, Clarisse Maurin, Elizabeth Orrin, Magdalena Martinez-Queipo, Ellie Rashidghamat, Christos Tziotzios, Alexandros Onoufriadis, Mei Chen, Lucas Chan, Farzin Farzaneh, Marcela Del Rio, Jakub Tolar, Johann W. Bauer, Fernando Larcher, Michael N. Antoniou, Alain Hovnanian, Adrian J. Thrasher, Jemima E. Mellerio, Waseem Qasim, John A. Mcgrath

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Abstract

BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION. ClincalTrials.gov NCT02493816.

Original language	English
Article number	:e126243
Journal	JCI Insight
Volume	4
Issue number	11
Early online date	6 Jun 2019
DOIs	https://doi.org/10.1172/jci.insight.126243
Publication status	Published - 6 Jun 2019

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Lwin, S. M., Syed, F., Di, W., Kadiyirire, T., Liu, L., Guy, A., Petrova, A., Abdul-Wahab, A., Reid, F., Phillips, R., Elstad, M., Georgiadis, C., Aristodemou, S., Lovell, P. A., Mcmillan, J. R., Mee, J., Miskinyte, S., Titeux, M., Ozoemena, L., ... Mcgrath, J. A. (2019). Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa. JCI Insight, 4(11), Article :e126243. https://doi.org/10.1172/jci.insight.126243

@article{a6f8b0ce00204bc295c00fdc6a8160dc,

title = "Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa",

abstract = "BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION. ClincalTrials.gov NCT02493816.",

author = "Lwin, {Su M.} and Farhatullah Syed and Wei-li Di and Tendai Kadiyirire and Lu Liu and Alyson Guy and Anastasia Petrova and Alya Abdul-Wahab and Fiona Reid and Rachel Phillips and Maria Elstad and Christos Georgiadis and Sophia Aristodemou and Lovell, {Patricia A.} and Mcmillan, {James R.} and John Mee and Snaigune Miskinyte and Matthias Titeux and Linda Ozoemena and Rashida Pramanik and Sonia Serrano and Racheal Rowles and Clarisse Maurin and Elizabeth Orrin and Magdalena Martinez-Queipo and Ellie Rashidghamat and Christos Tziotzios and Alexandros Onoufriadis and Mei Chen and Lucas Chan and Farzin Farzaneh and {Del Rio}, Marcela and Jakub Tolar and Bauer, {Johann W.} and Fernando Larcher and Antoniou, {Michael N.} and Alain Hovnanian and Thrasher, {Adrian J.} and Mellerio, {Jemima E.} and Waseem Qasim and Mcgrath, {John A.}",

year = "2019",

month = jun,

day = "6",

doi = "10.1172/jci.insight.126243",

language = "English",

volume = "4",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "11",

}

Lwin, SM, Syed, F, Di, W, Kadiyirire, T, Liu, L, Guy, A, Petrova, A , Abdul-Wahab, A , Reid, F , Phillips, R , Elstad, M, Georgiadis, C, Aristodemou, S, Lovell, PA, Mcmillan, JR, Mee, J, Miskinyte, S, Titeux, M, Ozoemena, L, Pramanik, R, Serrano, S, Rowles, R, Maurin, C, Orrin, E, Martinez-Queipo, M, Rashidghamat, E , Tziotzios, C , Onoufriadis, A, Chen, M, Chan, L , Farzaneh, F, Del Rio, M, Tolar, J, Bauer, JW, Larcher, F, Antoniou, MN, Hovnanian, A, Thrasher, AJ, Mellerio, JE, Qasim, W & Mcgrath, JA 2019, 'Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa', JCI Insight, vol. 4, no. 11, :e126243. https://doi.org/10.1172/jci.insight.126243

TY - JOUR

T1 - Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa

AU - Lwin, Su M.

AU - Syed, Farhatullah

AU - Di, Wei-li

AU - Kadiyirire, Tendai

AU - Liu, Lu

AU - Guy, Alyson

AU - Petrova, Anastasia

AU - Abdul-Wahab, Alya

AU - Reid, Fiona

AU - Phillips, Rachel

AU - Elstad, Maria

AU - Georgiadis, Christos

AU - Aristodemou, Sophia

AU - Lovell, Patricia A.

AU - Mcmillan, James R.

AU - Mee, John

AU - Miskinyte, Snaigune

AU - Titeux, Matthias

AU - Ozoemena, Linda

AU - Pramanik, Rashida

AU - Serrano, Sonia

AU - Rowles, Racheal

AU - Maurin, Clarisse

AU - Orrin, Elizabeth

AU - Martinez-Queipo, Magdalena

AU - Rashidghamat, Ellie

AU - Tziotzios, Christos

AU - Onoufriadis, Alexandros

AU - Chen, Mei

AU - Chan, Lucas

AU - Farzaneh, Farzin

AU - Del Rio, Marcela

AU - Tolar, Jakub

AU - Bauer, Johann W.

AU - Larcher, Fernando

AU - Antoniou, Michael N.

AU - Hovnanian, Alain

AU - Thrasher, Adrian J.

AU - Mellerio, Jemima E.

AU - Qasim, Waseem

AU - Mcgrath, John A.

PY - 2019/6/6

Y1 - 2019/6/6

N2 - BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION. ClincalTrials.gov NCT02493816.

AB - BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION. ClincalTrials.gov NCT02493816.

UR - http://www.scopus.com/inward/record.url?scp=85070661349&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.126243

DO - 10.1172/jci.insight.126243

M3 - Article

SN - 2379-3708

VL - 4

JO - JCI Insight

JF - JCI Insight

IS - 11

M1 - :e126243

ER -

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa

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