Taking Stem Cells Beyond Discovery: A Milestone in the Reporting of Regulatory Requirements for Cell Therapy

I n this issue of Stem Cells and Development, Ra et al. provide a detailed description of the preclinical studies leading up to their initial clinical safety trial for the treatment of spinal cord injury patients with adipose-derived mesenchymal stromal/stem cells (AdMSCs) [1]. The article provides a substantial body of data employing a wide range of in vitro and in vivo assays conducted under Good Laboratory Practices. The list is extensive: sterility of the human AdMSC (hAdMSC) product was determined based on assays of bacterial, endotoxin, mycoplasma, and viral contamination. Flow cytometry characterized the immunophenotype of the hAdMSCs as a function of serial passage. Histochemical and immunohistochemical staining methods documented the hAdMSC adipogenic, chondrogenic, myogenic, neuronal, and osteogenic differentiation potential. Karyotyping and single-nucleotide polymorphism analyses confirmed the genome stability of the culture expanded hAdMSCs. Additional in vivo toxicology studies were performed in cohorts of immunodeficient male and female mice. In one experiment, cohorts received intravenous injections of increasing concentrations of hAdMSCs via the tail vein and were monitored over 13 weeks for evidence of altered weight gain, food intake, and water consumption. At autopsy, evidence of pathology was assessed based on serum and urine chemistry and histology of the major organs. In a second experiment, cohorts of were injected subcutaneously with increasing doses of hAdMSC and monitored over 26 weeks for evidence of tumor formation. Separate cohorts injected with human lung or melanoma cell lines served as positive controls. With the evidence accrued through these analyses, the investigators progressed to a Phase I safety study in 8 male spinal cord injury patients under an Investigational New Drug (IND) application approved by the Korean Food and Drug Administration and a protocol approved by their hospital Institutional Review Board.

Despite the fact that this article recapitulates previous published in vitro analyses of hAdMSCs [2,3] and its in vivo animal studies document largely negative outcomes, Ra et al. merit attention. Although several previous studies have evaluated the oncogenic potential of implanted hAdMSCs (e.g., [4 –9]), the article by Ra et al. is among the first articles to provide a detailed report of the data required to fulfill regulatory approval for an hAdMSC IND and Phase I safety study [1]. This represents an important milestone in the maturing field of cell therapeutics. It documents the steps taken by biotech and academic investigators to insure that their clinical stem cell research will be conducted with the same rigor that has been used historically to oversee the development of traditional pharmaceuticals.

The dialogue between regulatory agencies and individual companies or university laboratories regarding the development of stem cell therapeutics often remains confidential. Sometimes, this privacy relates to intellectual property issues surrounding the cell product. Alternatively, there may be financial incentives to maintain secrecy around the manufacturing process. As a result, while experiments are conducted by the investigators and their outcomes reported to federal regulatory authorities, the scientific community and the public remain outside the conversation. While this is understandable from a commercial perspective, it does not best serve the long-term development of stem cell therapeutics. In contrast, a detailed, peer-reviewed public record from multiple laboratories and companies will provide an accumulating body of evidence that these findings are reproducible, safe, and efficacious.

While the developmental process for cell therapeutics will need to address rigorous and defined questions from the regulatory authorities, they will not necessarily meet current standards for hypothesis-driven, mechanism-based studies. Despite this, articles documenting the ongoing development of cell-based therapeutics at the regulatory level provide tremendous value to the field of translational research and need to gain acceptance in the peer-reviewed literature. Studies similar to this pioneering work by Ra et al. are needed to reproduce not only the safety evaluation of undifferentiated hAdMSCs but also that of the cells in their differentiated states, without and without the combination of diverse biomaterial scaffolds [1]. Such a body of literature will provide critical evidence for future meta-analyses evaluating the safety, efficacy, and outcome measures of clinical trials using hAdMSCs for a variety of ailments [10].