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Stem cell therapy for bronchopulmonary dysplasia: bench to bedside translation.

ABSTRACT: Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting very premature infants, is a major cause of mortality and long-term morbidities despite of current progress in neonatal intensive care medicine. Though there has not been any effective treatment or preventive strategy for BPD, recent stem cell research seems to support the assumption that stem cell therapy could be a promising and novel therapeutic modality for attenuating BPD severity. This review summarizes the recent advances in stem cell research for treating BPD. In particular, we focused on the preclinical data about stem cell transplantation to improve the lung injury using animal models of neonatal BPD. These translational research provided the data related with the safety issue, optimal type of stem cells, optimal timing, route, and dose of cell transplantation, and potency marker of cells as a therapeutic agent. Those are essential subjects for the approval and clinical translation. In addition, the successful phase I clinical trial results of stem cell therapies for BPD are also discussed.

SUBMITTER: Ahn SY

PROVIDER: S-EPMC4414632 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Stem cell therapy for bronchopulmonary dysplasia: bench to bedside translation.

Ahn So Yoon SY Chang Yun Sil YS Park Won Soon WS

Journal of Korean medical science 20150415 5

Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting very premature infants, is a major cause of mortality and long-term morbidities despite of current progress in neonatal intensive care medicine. Though there has not been any effective treatment or preventive strategy for BPD, recent stem cell research seems to support the assumption that stem cell therapy could be a promising and novel therapeutic modality for attenuating BPD severity. This review summarizes the recent advances ...[more]

PMID: 25931779

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Project description:Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the CTNS gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns-/- mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the CTNS cDNA, pCCL-CTNS, and showed its efficacy in Ctns-/- mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34+ HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis.

Dataset Information

Stem cell therapy for bronchopulmonary dysplasia: bench to bedside translation.

Publications

Stem cell therapy for bronchopulmonary dysplasia: bench to bedside translation.

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