To date, almost 2600 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our November 2017 update, we have entries on 2597 trials undertaken in 38 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and the genes that have been transferred. Details of the analyses presented, and our searchable database are available via The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in gene therapy clinical trials around the world, and discuss key trends since the previous review, namely the use of chimeric antigen receptor T cells for the treatment of cancer and advancements in genome editing technologies, which have the potential to transform the field moving forward.

Gene therapy clinical trials worldwide to 2017: An update

Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.

/pdf/phase-1-clinical-study-of-an-embryonic-stem-cell-derived-4vohryqfba.pdf

Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration.

Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns. In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine. We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues. Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine. This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.

/pdf/ethical-and-safety-issues-of-stem-cell-based-therapy-hp0he22kcw.pdf

Ethical and Safety Issues of Stem Cell-Based Therapy.

https://www.cell.com/cell-stem-cell/pdf/S1934-5909(20)30460-4.pdf

Pluripotent Stem Cell-Based Cell Therapy—Promise and Challenges

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.

/pdf/induced-pluripotent-stem-cells-in-disease-modelling-and-drug-5eejuofnsg.pdf

Induced pluripotent stem cells in disease modelling and drug discovery.

We assessed the feasibility of transplanting a sheet of retinal pigment epithelial (RPE) cells differentiated from induced pluripotent stem cells (iPSCs) in a patient with neovascular age-related macular degeneration. The iPSCs were generated from skin fibroblasts obtained from two patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. The RPE cells and the iPSCs from which they were derived were subject to extensive testing. A surgery that included the removal of the neovascular membrane and transplantation of the autologous iPSC-derived RPE cell sheet under the retina was performed in one of the patients. At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present. (Funded by Highway Program for Realization of Regenerative Medicine and others; University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000011929.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1608368

Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration

Transplantation of Autologous induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets for Exudative Age Related Macular Degeneration : A Pilot Clinical Study


 Background:
 The models for predicting cardiovascular events, including medication data such as dosage and the number of medications, have not been well studied. This study aimed to develop a model, including medication data, for predicting cardiovascular events within one year after discharge in acute decompensated heart failure (ADHF) patients with decreased renal function.
 
 
 Methods
 This study included 443 first-time admitted ADHF patients with decreased renal function in the Showa University Fujigaoka Hospital between January 2015 and December 2019. Decreased renal function was defined as an eGFR < 60 mL/min/1.73 m
 2
 at discharge. The primary outcome was cardiovascular events (cardiovascular death and first heart failure rehospitalization) within one year after discharge. The model for predicting events was developed using predictive factors extracted by multivariate analysis. The cardiovascular events curves were visualized using the Kaplan-Meier method and estimated using a log-rank test.
 
 
 Results
 The incidence of cardiovascular events was 20.1%. By multivariate analysis, atrial fibrillation (AF), weight loss < 5% during admission, brain natriuretic peptide (BNP) ≥ 200 pg/mL at discharge, polypharmacy (≥ 10 drugs), and beta-blockers use below the maintenance dosage were significantly associated with an increased risk of cardiovascular events. The hazard ratios of the five factors for the cardiovascular events were scored (AF, weight loss, polypharmacy, and beta-blockers dosage = 1 point; BNP = 2 points) and patients divided into three groups. The cardiovascular events rate in the high-risk (≥ 4 points) group was four times as high as the rate in the low-risk (≤ 2 point) group (one-year events rate: 41.0% vs 9.2%, p < 0.001, Figure).
 
 
 Conclusions
 The developed model for cardiovascular events, including polypharmacy and beta-blockers dosage, will be useful for planning more aggressive and earlier management in ADHF patients with decreased renal function.
 
 
 


Kanako Fujita

Papers

Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration

Transplantation of Autologous induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets for Exudative Age Related Macular Degeneration : A Pilot Clinical Study

Abstract 11074: A Model for Predicting Cardiovascular Events in Acute Decompensated Heart Failure Patients With Decreased Renal Function