Biodistribution studies for cell therapy products: Current status and issues

Kamiyama, Yoshiteru; Naritomi, Yoichi; Moriya, Yuu; Yamamoto, Satoshi; Kitahashi, Tsukasa; Maekawa, Toshihiko; Yahata, Masahiro; Hanada, Takeshi; Uchiyama, Asako; Noumaru, Akari; Koga, Yoshiyuki; Higuchi, Tomoaki; Ito, Masahiko; Komatsu, Hiroyuki; Miyoshi, Sosuke; Kimura, Sadaaki; Umeda, Nobuhiro; Fujita, Eriko; Tanaka, Naoko; Sugita, Taku; Takayama, Seiji; Kurogi, Akihiko; Yasuda, Satoshi; Sato, Yoji

doi:10.1016/j.reth.2021.06.005

Cited by 16 publications

(12 citation statements)

References 104 publications

(167 reference statements)

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“…The in vivo distribution of MSCs is closely related to the transplantation route [ 33 ]. The distribution of MSCs after intravenous infusion has been reported in many studies [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

Wu,

Ma,

Yang

et al. 2023

Stem Cell Res Ther

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Background Safety evaluations in preclinical studies are needed to confirm before translating a cell-based product into clinical application. We previously developed a serum-free, xeno-free, and chemically defined media (S&XFM–CD) for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs), and demonstrated that intraperitoneal administration of UCMSCs in S&XFM–CD (UCMSCS&XFM−CD) exhibited better therapeutic effects than UCMSCs in serum-containing media (SCM, UCMSCSCM). However, a comprehensive investigation of the safety of intraperitoneal UCMSCS&XFM−CD treatment should be performed before clinical applications. Methods In this study, the toxicity, immunogenicity and biodistribution of intraperitoneally transplanted UCMSCS&XFM−CD were compared with UCMSCSCM in rats via general vital signs, blood routine, blood biochemistry, subsets of T cells, serum cytokines, pathology of vital organs, antibody production and the expression of human-specific gene. The tumorigenicity and tumor-promoting effect of UCMSCS&XFM−CD were compared with UCMSCSCM in nude mice. Results We confirmed that intraperitoneally transplanted UCMSCS&XFM−CD or UCMSCSCM did not cause significant changes in body weight, temperature, systolic blood pressure, diastolic blood pressure, heart rate, blood routine, T lymphocyte subsets, and serum cytokines, and had no obvious histopathology change on experimental rats. UCMSCS&XFM−CD did not produce antibodies, while UCMSCSCM had very high chance of antibody production to bovine serum albumin (80%) and apolipoprotein B-100 (60%). Furthermore, intraperitoneally injected UCMSCS&XFM−CD were less likely to be blocked by the lungs and migrated more easily to the kidneys and colon tissue than UCMSCSCM. In addition, UCMSCS&XFM−CD or UCMSCSCM showed no obvious tumorigenic activity. Finally, UCMSCS&XFM−CD extended the time of tumor formation of KM12SM cells, and decreased tumor incidence than that of UCMSCSCM. Conclusions Taken together, our data indicate that UCMSCS&XFM−CD display an improved safety performance and are encouraged to use in future clinical trials.

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“…The in vivo distribution of MSCs is closely related to the transplantation route [ 33 ]. The distribution of MSCs after intravenous infusion has been reported in many studies [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

Wu,

Ma,

Yang

et al. 2023

Stem Cell Res Ther

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“…Against this background, advanced gene and cell therapies are now able to offer a “curative,” rather than merely substitutive treatment, as they are capable of correcting the mutational root cause of many conditions, particularly congenital ones, both monogenic and polygenic [ 86 , 87 , 88 , 89 ] Congenital coagulopathies, many of them rare diseases like hemophilia or ultra-rare diseases like FVa deficiency, may benefit from these developments.…”

Section: Discussionmentioning

confidence: 99%

High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

Bernal

Peláez

Alías

et al. 2021

IJMS

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Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.

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“…Biodistribution analysis is an important safety evaluation method for determining the residual amount, residual position, and clearance time of biopharmaceuticals such as cell, gene, and EV therapies [98][99][100]. To evaluate safety during biodistribution assessments of gene and cell therapies, globally established preclinical studies are performed [74].…”

Section: Biodistribution Testsmentioning

confidence: 99%

Characteristics of Extracellular Vesicles and Preclinical Testing Considerations Prior to Clinical Applications

2022

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Cell therapy products have significant limitations, such as storage instability, difficulties with transportation, and toxicity issues such as tumorigenicity and immunogenicity. Extracellular vesicles (EVs) secreted from cells show potential for therapeutic agent development. EVs have not been widely examined as investigational drugs, and non-clinical studies for the clinical approval of EV therapeutic agents are challenging. EVs contain various materials, such as DNA, cellular RNA, cytokines, chemokines, and microRNAs, but do not proliferate or divide like cells, thus avoiding safety concerns related to tumorigenicity. However, the constituents of EVs may induce the proliferation of normal cells; therefore, the suitability of vesicles should be verified through non-clinical safety evaluations. In this review, the findings of non-clinical studies on EVs are summarized. We describe non-clinical toxicity studies of EVs, which should be useful for researchers who aim to develop these vesicles into therapeutic agents. A new method for evaluating the immunotoxicity and tumorigenicity of EVs should also be developed.

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Biodistribution studies for cell therapy products: Current status and issues

Cited by 16 publications

References 104 publications

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

Characteristics of Extracellular Vesicles and Preclinical Testing Considerations Prior to Clinical Applications

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