Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics

Cripe, Timothy P.; Hutzen, Brian; Currier, Mark A.; Chen, Chun-Yu; Glaspell, Andrea M; Sullivan, Grace C; Hurley, Julia M; Deighen, Mackenzie R; Venkataramany, Akila S; Mo, Xiaokui; Stanek, Joseph; Miller, Anthony R.; Wijeratne, Saranga; Magrini, Vincent; Mardis, Elaine R.; Mendell, Jerry R.; Chandler, Dawn S.; Wang, Pin-Yi

doi:10.1126/sciadv.abm1890

Cited by 10 publications

(7 citation statements)

References 34 publications

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“…Several previous studies have addressed the relationship between gene therapy and expressed protein levels. For example, it was reported that a single dose of AAV gene therapy resulted in sustained serum levels of immunotherapeutic proteins 38 . The study reported that the gene therapy resulted in sustained protein expression in the systemic circulation for up to 1 year in mice.…”

Section: Discussionmentioning

confidence: 99%

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Rojsajjakul,

Hordeaux,

Choudhury

et al. 2023

Commun Biol

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Deficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich’s ataxia (FRDA). It results primarily through epigenetic silencing of the FXN gene by GAA triplet repeats on intron 1 of both alleles. GAA repeat lengths are most commonly between 600 and 1200 but can reach 1700. A subset of approximately 3% of FRDA patients have GAA repeats on one allele and a mutation on the other. FRDA patients die most commonly in their 30s from heart disease. Therefore, increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. However, this presented a formidable bioanalytical challenge in quantification of proteins with almost identical sequences. This could be overcome by the development of a species-specific quantitative mass spectrometry-based method, which has revealed for the first time, robust transgene-specific human protein expression in monkey heart tissue. The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.

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Section: Discussionmentioning

confidence: 99%

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Rojsajjakul,

Hordeaux,

Choudhury

et al. 2023

Commun Biol

View full text Add to dashboard Cite

show abstract

“…Several previous studies have addressed the relationship between gene therapy and expressed protein levels. For example, it was reported that a single dose of AAV gene therapy resulted in sustained serum levels of immunotherapeutic proteins 34 . The study reported that the gene therapy resulted in sustained protein expression in the systemic circulation for up to 1 year in mice.…”

Section: Discussionmentioning

confidence: 99%

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Blair

Rojsajjakul

Hordeaux

et al. 2023

Preprint

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Deficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich’s ataxia (FRDA). It results primarily by epigenetic silencing the FXN gene due to up to 1400 GAA triplet repeats in intron 1 of both alleles of the gene; a subset of approximately 3% of FRDA patients have a mutation on one allele. FRDA patients die most commonly in their 30s from heart disease. Therefore, increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. However, this presented a formidable bioanalytical challenge in quantification of proteins with almost identical sequences. This was overcome by development of a species-specific quantitative mass spectrometry-based method, which revealed for the first time, robust transgene-specific human protein expression in monkey heart tissue. The dose response was non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.

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“…In a study by Buck and Wijnholds, the advantages and disadvantages of using recombinant AAV vectors in gene therapy for eye diseases have been discussed [53]. Briefly, AAV vector (1) can express its transgene in a few days to a few weeks and reach its maximum expression in 4-6 weeks [68]; (2) the virus enters its genome into the cell nucleus in episomal form and can express its genome without integration into the host genome [55]; (3) it can express its gene in a longterm manner. It has been observed that gene expression in dogs has continued for up to 10 years [69]; (4) AAV can have different capsids, resulting in different virus serotypes with (5) AAV can spread efficiently in the tissues and infect a large part of the target tissue.…”

Section: Gene Therapy Vectorsmentioning

confidence: 99%

X-Linked Retinitis Pigmentosa Gene Therapy: Preclinical Aspects

Mansouri

2022

Ophthalmol Ther

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The most common inherited eye disease is retinitis pigmentosa (RP). X-linked RP (XLRP) is one of the most severe types of RP, with a considerable disease burden. Patients with XLRP experience a decrease in their vision and become blind in their 4th decade of life, causing much morbidity after starting a rather normal life. Treatment of XLRP remains challenging, and current treatments are not effective enough in restoring vision. Gene therapy of XLRP, capable of restoring the functional RPGR gene, showed promising results in preclinical studies and clinical trials; however, to date, no approved product has entered the market. The development of a gene therapy product needs through preliminary assessment of the drug in animal models before administration to humans. In this article, we reviewed the genetic pathology of XLRP, along with the preclinical aspects of the XLRP gene therapy, animal models, associated assessments, and future challenges and directions.

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Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics

Cited by 10 publications

References 34 publications

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

X-Linked Retinitis Pigmentosa Gene Therapy: Preclinical Aspects

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