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Are cell-based therapies for kidney disease safe? A systematic review of preclinical evidence
Milos Mihajlovic1, Kimberley E Wever2, Thom K van der Made3
1Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
Abstract:
The number of individuals affected by acute kidney injury (AKI) and chronic kidney disease (CKD) is constantly rising. In light of the limited availability of treatment options and their relative inefficacy, cell based therapeutic modalities have been studied. However, not many efforts are put into safety evaluation of such applications. The aim of this study was to review the existing published literature on adverse events reported in studies with genetically modified cells for treatment of kidney disease. A systematic review was conducted by searching PubMed and EMBASE for relevant articles published until June 2018. The search results were screened and relevant articles selected using pre-defined criteria, by two researchers independently. After initial screening of 6894 abstracts, a total number of 97 preclinical studies was finally included for full assessment. Of these, 61 (63%) presented an inappropriate study design for the evaluation of safety parameters. Only 4 studies (4%) had the optimal study design, while 32 (33%) showed sub-optimal study design with either direct or indirect evidence of adverse events. The high heterogeneity of studies included regarding cell type and number, genetic modification, administration route, and kidney disease model applied, combined with the consistent lack of appropriate control groups, makes a reliable safety evaluation of kidney cell-based therapies impossible. Only a limited number of relevant studies included looked into essential safety-related outcomes, such as inflammatory (48%), tumorigenic and teratogenic potential (12%), cell biodistribution (82%), microbiological safety with respect to microorganism contamination and latent viruses' reactivation (1%), as well as overall well-being and animal survival (19%). In conclusion, for benign cell-based therapies, well-designed pre-clinical studies, including all control groups required and good manufacturing processes securing safety, need to be done early in development. Preferably, this should be performed side by side with efficacy evaluation and according to the official guidelines of leading health organizations.
Insights
Preclinical studies for kidney disease cell therapies often lack safety evaluations. Most studies have flawed designs, hindering reliable assessment of adverse events and making cell-based treatments for kidney disease unsafe.
Area of Science:
- Nephrology
- Regenerative Medicine
- Biotechnology
Background:
- Rising incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) necessitates novel treatments.
- Cell-based therapies offer potential but require rigorous safety evaluation.
- Current research inadequately addresses adverse events in preclinical kidney disease models.
Purpose of the Study:
- To systematically review adverse events reported in preclinical studies of genetically modified cells for kidney disease treatment.
- To assess the quality of study designs used for evaluating the safety of these cell-based therapies.
- To identify gaps in safety assessments for regenerative medicine approaches in nephrology.
Main Methods:
- Systematic literature review of PubMed and EMBASE databases up to June 2018.
- Screening of 6894 abstracts, with 97 preclinical studies included for full assessment.
- Independent review by two researchers using pre-defined inclusion criteria.
Main Results:
- 63% of studies had inappropriate designs for safety evaluation; only 4% used optimal designs.
- 33% of studies showed sub-optimal designs with evidence of adverse events.
- Significant heterogeneity in cell types, genetic modifications, and models, coupled with lack of control groups, impedes reliable safety assessment.
Conclusions:
- Current preclinical studies for kidney cell-based therapies are insufficient for reliable safety evaluation.
- Well-designed preclinical studies with appropriate controls and adherence to Good Manufacturing Practices are crucial.
- Safety evaluations should be integrated early in therapeutic development, alongside efficacy studies and according to regulatory guidelines.
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