RESTORE Survey on the Public Perception of Advanced Therapies and ATMPs in Europe — Why the European Union Should Invest More!

Advanced therapy medicinal products (ATMPs) are potential game changers in modern medical care with an anticipated major impact for patients and society. They are a new drug class often referred to as "living drugs," and are based on complex components such as vectors, cells and even tissues. The production of such ATMPs involves innovative biotechnological methods. In this survey, we have assessed the perception of European citizens regarding ATMPs and health care in Europe, in relation to other important topics, such as safety and security, data protection, climate friendly energy supply, migration, and others. A crucial question was to determine to what extent European citizens wish to support public funding of innovations in healthcare and reimbursement strategies for ATMPs. To answer this, we conducted an online survey in 13 European countries (representative of 85.3% of the entire EU population including the UK in 2020), surveying a total of 7,062 European citizens. The survey was representative with respect to adult age groups and gender in each country. Healthcare had the highest ranking among important societal topics. We found that 83% of the surveyed EU citizens were in support of more public funding of technologies in the field of ATMPs. Interestingly, 74% of respondents are in support of cross-border healthcare for patients with rare diseases to receive ATMP treatments and 61% support the reimbursement of very expensive ATMPs within the European health care system despite the current lack of long-term efficacy data. In conclusion, healthcare is a top ranking issue for European Citizens, who additionally support funding of new technologies to enable the wider application of ATMPs in Europe

Mitigation of Lethal Radiation Syndrome in Mice by Intramuscular Injection of 3D Cultured Adherent Human Placental Stromal Cells.

Exposure to high lethal dose of ionizing radiation results in acute radiation syndrome with deleterious systemic effects to different organs. A primary target is the highly sensitive bone marrow and the hematopoietic system. In the current study C3H/HeN mice were total body irradiated by 7.7 Gy. Twenty four hrs and 5 days after irradiation 2×10(6) cells from different preparations of human derived 3D expanded adherent placental stromal cells (PLX) were injected intramuscularly. Treatment with batches consisting of pure maternal cell preparations (PLX-Mat) increased the survival of the irradiated mice from ∼27% to 68% (P<0.001), while cell preparations with a mixture of maternal and fetal derived cells (PLX-RAD) increased the survival to ∼98% (P<0.0001). The dose modifying factor of this treatment for both 50% and 37% survival (DMF50 and DMF37) was∼1.23. Initiation of the more effective treatment with PLX-RAD injection could be delayed for up to 48 hrs after irradiation with similar effect. A delayed treatment by 72 hrs had lower, but still significantly effect (p<0.05). A faster recovery of the BM and improved reconstitution of all blood cell lineages in the PLX-RAD treated mice during the follow-up explains the increased survival of the cells treated irradiated mice. The number of CD45+/SCA1+ hematopoietic progenitor cells within the fast recovering population of nucleated BM cells in the irradiated mice was also elevated in the PLX-RAD treated mice. Our study suggests that IM treatment with PLX-RAD cells may serve as a highly effective "off the shelf" therapy to treat BM failure following total body exposure to high doses of radiation. The results suggest that similar treatments may be beneficial also for clinical conditions associated with severe BM aplasia and pancytopenia

Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

Abstract Background Most current cell‐based regenerative therapies are based on the indirect induction of the affected tissues repair. Xenogeneic cell‐based treatment with expanded human placenta stromal cells, predominantly from fetal origin (PLX‐RAD cells), were shown to mitigate significantly acute radiation syndrome (ARS) following high dose irradiation in mice, with expedited regain of weight loss and haematopoietic function. The current mechanistic study explores the indirect effect of the secretome of PLX‐RAD cells in the rescue of the irradiated mice. Methods The mitigation of the ARS was investigated following two intramuscularly (IM) injected 2 × 106 PLX‐RAD cells, 1 and 5 days following 7.7 Gy irradiation. The mice survival rate and their blood or bone marrow (BM) cell counts were followed up and correlated with multiplex immunoassay of a panel of related human proteins of PLX‐RAD derived secretome, as well as endogenous secretion of related mouse proteins. PLX‐RAD secretome was also tested in vitro for its effect on the induction of the migration of BM progenitors. Results A 7.7 Gy whole body mice irradiation resulted in ~25% survival by 21 days. Treatment with two IM injections of 2 × 106 PLX‐RAD cells on days 1 and 5 after irradiation mitigated highly significantly the subsequent lethal ARS, with survival rate increase to nearly 100% and fast regain of the initial weight loss (P 500 pg/mL, while MCP‐3, ENA, Eotaxin and fractalkine levels ranged between ~60–160pg/mL. The detected radiation‐induced PLX‐RAD secretome correlated well with the timing of the fast haematopoiesis regeneration. The radiation‐induced PLX‐RAD secretome seemed to reinforce the delayed high levels secretion of related mouse endogenous cytokines, including GCSF, KC, MCP‐1 and IL‐6. Additional supportive in vitro studies also confirmed the ability of cultured PLX‐RAD secretome to induce accelerated migration of BM progenitors. Conclusions A well‐regulated and orchestrated secretion of major pro‐regenerative BM supporting secretome in high dose irradiated mice, treated with xenogeneic IM injected PLX‐RAD cells, can explain the observed mitigation of ARS. This seemed to coincide with faster haematopoiesis regeneration, regain of severe weight loss and the increased survival rate. The ARS‐related stress signals activating the IM injected PLX‐RAD cells for the remote secretion of the relevant human proteins deserve further investigation

The effect of IM injection of PLX-RAD cells on days 1 and 5 after radiation on the number of nucleated cells from whole BM and the ratio of progenitors within this cell population.

<p>(A) Up to day 9 after irradiation, the number of the nucleated BM cells decreased sharply in both arms, followed by a faster gain in the number of total nucleated BM cells in the PLX-RAD treated animals, as compared to the vehicle controls. By day 30 a full recovery of the number of nucleated BM cells was recorded only in the group of irradiated PLX-RAD treated mice. (B) FACS analysis of the kinetics of changes in the % of CD45⁺/Sca-1⁺ of the nucleated cells (representing the progenitor cells population) was tested in both arms of mice irradiated by 7.7 Gy, PLX-RAD or vehicle control treated. Maximal increase in the proportion of these cells due to the radiation exposure was recorded on day 9 in both groups, before the onset of the critical phase of the hematopoietic syndrome. Significance: * = P<0.05, ** = P<0.01.</p

The effect of IM PLX-RAD injection on the survival of 7.7 Gy total body irradiated mice.

<p>The setup of the experiment arms is described in (A). PLX-RAD cells (2×10⁶) were injected IM twice, 1^st injection was done 24 or 48 or 72 hrs and 2^nd injection was done on day 5 after irradiation. In another arm only a single injection on day 5 was given. The data presented are based on merged separate experimental repetitions. The total number of animals in each arm is shown in the legend. The follow-up of mice survival between the different schedules of treatment is shown in (B). The BM and blood cells profile of the surviving mice at the end of the experiments on day 23 is shown in (C). Significance: * = P<0.05, ** = P<0.01, **** = P<0.001, ***** = P<0.0001.</p

The effect of IM PLX-Mat and PLX-RAD injection on the survival of 7.7 Gy total body irradiated mice.

<p>The setup of the experiment is described in (A). 2×10⁶ PLX-RAD or PLX-Mat cells were injected IM twice, 1^st injection delivered 24 hrs and 2^nd injection on day 5 after irradiation. The follow-up of mice survival is shown in (B). Weight changes for the group of IM injected mice at day 1 and 5 after irradiation are presented in (C). The BM and blood counts of the surviving animal at the end of the experiment at day 23 are presented in (D). Significance: * = P<0.05, ** = P<0.01*** = P<0.005, **** = P<0.001, ***** = P<0.0001.</p