Allometric-like scaling of AAV gene therapy for systemic protein delivery

Burr, Alexandra; Erickson, Patrick; Bento, Raphaela; Shama, Kariman; Roth, Charles M.; Parekkadan, Biju

doi:10.1016/j.omtm.2022.10.011

Cited by 11 publications

(7 citation statements)

References 47 publications

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“…In addition, refined methods for dose selection based on, e.g., allometric scaling, would be advantageous. 52 …”

Section: Discussionmentioning

confidence: 99%

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

Haldrup,

Fabian-Jessing,

Jakobsen

et al. 2024

Molecular Therapy - Methods & Clinical Development

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“…In addition, refined methods for dose selection based on, e.g., allometric scaling, would be advantageous. 52 …”

Section: Discussionmentioning

confidence: 99%

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

Haldrup,

Fabian-Jessing,

Jakobsen

et al. 2024

Molecular Therapy - Methods & Clinical Development

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“…The study reported that the gene therapy resulted in sustained protein expression in the systemic circulation for up to 1 year in mice. Another study addressed the use of AAV gene therapy for systemic protein delivery, where it was suggested that further investigation into AAV expression at the tissue level would be the key to understanding how the system can be perturbed for increased potency 39 . In addition, a tunable switch system to control levels of gene therapy expression has been described, which could be used to optimize protein tissue levels 40 .…”

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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“…The method of scaling is dependent on the route of administration and the organ of tropism for the GT, as well as the measurability of the transgene product. Further refinement of the dose scaling approach should be explored, including inclusion of scaling factors identified in in vitro – in vivo correlation exercises 22 …”

Section: Model‐informed Approaches For Dose Selection and Optimizationmentioning

confidence: 99%

“…Further refinement of the dose scaling approach should be explored, including inclusion of scaling factors identified in in vitro-in vivo correlation exercises. 22…”

Section: Empirical and Allometric Scaling Based On Safetymentioning

confidence: 99%

Model‐Informed Approaches and Innovative Clinical Trial Design for Adeno‐Associated Viral Vector‐Based Gene Therapy Product Development: A White Paper

Mitra,

Ahmed,

Krishna

et al. 2023

Clin Pharma and Therapeutics

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The promise of viral vector‐based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life‐threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno‐associated virus (AAV) vector‐based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype–phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit–risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model‐informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV‐based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products.

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Allometric-like scaling of AAV gene therapy for systemic protein delivery

Cited by 11 publications

References 47 publications

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

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

Model‐Informed Approaches and Innovative Clinical Trial Design for Adeno‐Associated Viral Vector‐Based Gene Therapy Product Development: A White Paper

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