Pluripotent stem cell therapy for retinal diseases

Ahmed, Ishrat; Johnston, Robert J.; Singh, Mandeep S.

doi:10.21037/atm-20-4747

Cited by 16 publications

(10 citation statements)

References 118 publications

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“…Therefore, the potency of such cells strongly relates to the intended differentiation status (suitable markers and proliferation) and their intended MoA in each indication. Both ESCs and iPSCs have been used to treat retinal diseases like retinitis pigmentosa (RP) or age-related macular degeneration (AMD) (52). For such use it is critical to control the differentiation of the pluripotent cells into photoreceptor or retinal pigment epithelium (RPE) cells; potency testing in this case would combine differentiation assays/markers with methods assessing target cell type structure and functionality.…”

Section: Cell-based Atmpsmentioning

confidence: 99%

Potency testing of cell and gene therapy products

Salmikangas¹,

Reimer²,

Thirstrup

2023

Front. Med.

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Potency is one of the critical quality attributes of biological medicinal products, defining their biological activity. Potency testing is expected to reflect the Mechanism of Action (MoA) of the medicinal product and ideally the results should correlate with the clinical response. Multiple assay formats may be used, both in vitro assays and in vivo models, however, for timely release of the products for clinical studies or for commercial use, quantitative, validated in vitro assays are necessary. Robust potency assays are fundamental also for comparability studies, process validation and for stability testing. Cell and Gene Therapy Products (CGTs, also called Advanced Therapy Medicinal Products, ATMPs) are part of biological medicines, having nucleic acids, viral vectors, viable cells and tissues as starting material. For such complex products potency testing is often challenging and may require a combination of methods to address multiple functional mechanisms of the product. For cells, viability and cell phenotype are important attributes but alone will not be sufficient to address potency. Furthermore, if the cells are transduced with a viral vector, potency probably is related to the expression of the transgene but will also be dependent on the target cells and transduction efficiency/copy number of the transgene in the cells. Genome Editing (GE) together with other cell manipulations can result into multiple changes in the characteristics and activity of the cells, which should be all somehow captured by the potency testing. Non-clinical studies/models may provide valuable support for potency testing, especially for comparability testing. However, sometimes lack of suitable potency data may lead to situations where bridging clinical efficacy data are required to solve the problems of the potency testing, for example where comparability of different clinical batches is unclear. In this article the challenges of potency testing are discussed together with examples of assays used for different CGTs/ATMPs and the available guidance addressing differences between the European Union and the United States.

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Section: Cell-based Atmpsmentioning

confidence: 99%

Potency testing of cell and gene therapy products

Salmikangas¹,

Reimer²,

Thirstrup

2023

Front. Med.

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“… 2 Few treatment options are currently available to prevent or reverse the progression of RP; 3 however, targeted gene and cell-based therapies are being explored for the treatment of this condition. 4–6 …”

Section: Introductionmentioning

confidence: 99%

Elicitation of Health State Utility Values in Retinitis Pigmentosa by Time Trade-off in the United Kingdom

O'Brien¹,

Enstone²,

Bridge³

et al. 2023

CEOR

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Introduction Retinitis pigmentosa (RP) is an inherited retinal pathology associated with “night blindness” and progressive loss of peripheral vision, in some cases leading to complete blindness. Health state utility values are required for activities such as modelling disease burden or the cost-effectiveness of new interventions. The current study aimed to generate utility values for health states of varying levels of functional vision in RP, with members of the general public in the UK. Methods Five health states were defined according to standard clinical measures of visual ability. Health state descriptions were developed following interviews with patients with RP in the UK (n=5). Further interviews were conducted for confirmation with healthcare professionals with specific experience of managing patients with RP in the UK (n=2). Interviews with members of the general public in the UK were conducted to value health states. A time trade-off (TTO) process based on the established Measurement and Valuation of Health (MVH) protocol was used. Due to the ongoing COVID-19 pandemic, all interviews were web-enabled and conducted 1:1 by a trained moderator. Results In total, n=110 TTO interviews were conducted with members of the UK general public. Mean TTO utility values followed the logical and expected order, with increasing visual impairment leading to decreased utility. Mean values varied between 0.78 ± 0.20 (“moderate impairment”), and 0.33 ± 0.26 (“hand motion” to “no light perception”). Supplementary visual analogue scale (VAS) scores also followed the logical and expected order: mean VAS values varied between 47.95 ± 15.38 (“moderate impairment”) and 17.22 ± 12.49 in (“hand motion” to “no light perception”). Discussion These data suggest that individuals living with RP have substantially impaired quality of life. Utility values for RP have been elicited here using a method and sample that is suitable for economic modelling and health technology assessment purposes.

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“…A variety of different donor cell types have been evaluated for retinal cell transplantation 23,24 . For example, faterestricted retinal progenitor and photoreceptor precursor cells can be obtained from fetal donors and transplanted directly into patients [25][26][27][28][29] .…”

Section: Introductionmentioning

confidence: 99%

Biocompatibility of Human Induced Pluripotent Stem Cell–Derived Retinal Progenitor Cell Grafts in Immunocompromised Rats

et al. 2022

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Loss of photoreceptor cells is a primary feature of inherited retinal degenerative disorders including age-related macular degeneration and retinitis pigmentosa. To restore vision in affected patients, photoreceptor cell replacement will be required. The ideal donor cells for this application are induced pluripotent stem cells (iPSCs) because they can be derived from and transplanted into the same patient obviating the need for long-term immunosuppression. A major limitation for retinal cell replacement therapy is donor cell loss associated with simple methods of cell delivery such as subretinal injections of bolus cell suspensions. Transplantation with supportive biomaterials can help maintain cellular integrity, increase cell survival, and encourage proper cellular alignment and improve integration with the host retina. Using a pig model of retinal degeneration, we recently demonstrated that polycaprolactone (PCL) scaffolds fabricated with two photon lithography have excellent local and systemic tolerability. In this study, we describe rapid photopolymerization-mediated production of PCL-based bioabsorbable scaffolds, a technique for loading iPSC-derived retinal progenitor cells onto the scaffold, methods of surgical transplantation in an immunocompromised rat model and tolerability of the subretinal grafts at 1, 3, and 6 months of follow-up ( n = 150). We observed no local or systemic toxicity, nor did we observe any tumor formation despite extensive clinical evaluation, clinical chemistry, hematology, gross tissue examination and detailed histopathology. Demonstrating the local and systemic compatibility of biodegradable scaffolds carrying human iPSC-derived retinal progenitor cells is an important step toward clinical safety trials of this approach in humans.

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Pluripotent stem cell therapy for retinal diseases

Cited by 16 publications

References 118 publications

Potency testing of cell and gene therapy products

Potency testing of cell and gene therapy products

Elicitation of Health State Utility Values in Retinitis Pigmentosa by Time Trade-off in the United Kingdom

Biocompatibility of Human Induced Pluripotent Stem Cell–Derived Retinal Progenitor Cell Grafts in Immunocompromised Rats

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