New VISICORT study in Frontiers in Immunology

A new study has just been published by VISICORT researchers in the leading open access journal Frontiers in Immunology today, 20 November 2018. The study “Third-party allogeneic mesenchymal stromal cells prevent rejection in a pre-sensitized high-risk model of corneal transplantation” was completed by the National University of Ireland Galway team of Paul Lohan, Nick Murphy, Oliver Treacy, Kevin Lynch, Maurice Morcos, Bingling Chen, Aideen E. Ryan, Matthew D. Griffin and Thomas Ritter.

The study shows for the first time that intravenous administration of third-party allogeneic mesenchymal stromal cells (MSC from neither the new cornea recipient nor the cornea donor) results in distinct immune modulatory effects that overcome pre-existing anti-donor immunity to prolong rejection-free survival of corneal allografts in a laboratory model of high-risk corneal transplantation. The experimental cell therapy regimen described in the paper appears to be compatible with prior cryo-preservation and with co-administration of a relevant immunosuppressive drug. These findings open the door to clinical translation of “off-the-shelf” allogeneic MSC products for recipients of high-risk corneal transplants who continue to suffer from very poor long-term graft survival rates. The results of this experimental study have formed the basis of a regulatory submission for the VISICORT Phase Ib clinical trial in patients receiving a second or greater transplant who are at high risk of rejection. This trial will determine the safety and feasibility of co-administration of allogeneic MSC and MMF in the setting of high-risk corneal transplantation.

Immune outcomes in human CT studies edge near recruitment targets

A major task within the VISICORT project entails three multi-centre clinical studies to analyze bio-samples from more than 700 human subjects. This important aspect of VISICORT is being coordinated by Prof Dr Jesper Hjörtdal at the Aarhus University Hospital NBG in Denmark.

A multi-centre, “cross-sectional” clinical analysis study involves people (goal: 420 participants) with existing corneal transplants (CT) and healthy adult volunteers. Secondly, a multi-centre “prospective study” involves people who are new recipients of corneas (goal: 300 participants). In both studies, the participants are divided into groups in order to draw comparisons and draw inferences. The groups involved in these two studies include people with corneal transplant/s and healthy adult volunteers who are at the ophthalmology clinic for a check-up. The study subjects will be monitored, or “followed” for 3 years or more where repeat bio-samples, including blood and tears, are drawn periodically. Anyone willing, who can give informed consent and falls into one of the designated categories is able to take part in the study. Results of comprehensive ophthalmic examinations, corneal thickness measurements, and endothelial cell density tests will be stored in a secure clinical database system. These large studies aim to discover a biomarker present in the bio-samples which will help clinicians identify people who are at high risk for corneal transplant rejection episodes.

A third, multi-centre “clinical variables” study is also part of the VISICORT research plan. Here, people who have had a corneal transplant will be followed for a 3-year period where bio-samples will be collected and analyzed. Clinicians will be gaining knowledge regarding adverse immune outcomes from CT procedures in order to help validate and field test biomarker-based surveillance strategies. A highly detailed clinical follow-up will be available for the participants involved. A broad survey of clinical variables, immunosuppression practices, any complications and graft outcomes will be included.

Best practice standard care will be followed at each of the 5 clinical sites: Aarhus University Hospital (Denmark), Charité Universitätsmedizin Berlin (Germany), Royal Victoria Eye and Ear Hospital (Dublin, Republic of Ireland), Bristol Eye Hospital (U.K.) and the University Hospital Center (CHU) of Nantes (France).

At the moment, our recruitment targets are nearly achieved. In the cross-sectional clinical analysis study, we have collected bio-samples from 413 participants. We are nearly at our goal! For the multi-centre prospective study, 332 participants are involved. This exceeds our target. Finally, our clinical variable study has 588 people enrolled currently.*

*These figures were last updated on 23 January 2019.

VISICORT plenary meeting hosted by Charité and CRO

VISICORT partners met October 11 and 12, 2018 in Berlin to provide research updates and share future plans for the next six months of the project. After opening remarks by host Prof Uwe Pleyer of Charité and Andreas Hüser of CRO, Mark Sweetnam of Pintail Limited reminded partners of upcoming and remaining reporting obligations and deadlines. Coordinator Prof Matt Griffin of NUI Galway presented an update on the clinical trial planning, cell manufacturing process, regulatory submission and ethics and safety of MSC therapies. BioStór‘s Niall Walsh and Peadar MacGabhann raised important future considerations for the use of the VISICORT biobank and exploitation of these resources. Henrik Sejersen of Aarhus University Hospital reported upon the human subject enrolment, follow-up and clinical outcomes. A second clinical site tour will ensue to aid with data collection on all patients. Nico Degauque of the Center for Research in Transplantation and Immunology at INSERM presented an update on the multi-platform immune response profiles of human corneal transplantation. A new tool flow cytometry analysis tool CYBERSORT will be used in tandem with classical methods. Khadar Dudekula of SynthSys discussed her current targetted proteomics results and progress on the selection of protein biomarker candidates from the Fíos analyses. In addition, SynthSys PhD candidate Lisa Imrie presented her research project ideas for input from the VISICORT consortium and the potential exploitation of the VISICORT biobank. Fíos‘ Max Bylesjo shared recent advances in the integrated analysis of the proteomic and transcriptomic datasets. Pintail‘s Danielle Nicholson led a discussion on dissemination and potential amendments to the website and educational materials for patients. A tour of the Charité Research Organization ensued on the first day, and the meeting closed with a roundtable discussion to drive the project to completion. All aspects of the project requiring a follow up were addressed.

Cell therapy products present transport challenges in a rapidly changing world

VISICORT PI Peadar Mac Gabhann of Biostór was interviewed and presented a case study in cell therapy transports in the September 2018 CELL SERIES newsletter. In the interview, Peadar describes his experience within VISICORT: “Each transport of cell therapy products requires in-depth, case-by-case analysis & validation. This is very difficult to anticipate and plan in our rapidly changing world.”

Read the entire interview on page 7 here:  Cell Series Pre-Event Newsletter.

VISICORT clinical trial takes its first steps

VISICORT celebrates its first validation shipment of Stromal Cells from CCMI Galway to Charité Research Organisation (CRO) in Berlin for the commencement of the VISICORT clinical trial.

In the pictures below, Aoife Duffy, Manufacturing Manager at Centre for Cell Manufacturing Ireland (CCMI) at the National University of Ireland Galway is holding the first cell shipment. Cells were manufactured by CCMI in Galway and transport was performed by Biostór Ireland – a “Known Shipper” with the Irish Aviation Authority (IAA). This is the first of 7 shipments to be carried out during 2018 to establish the safety and tolerability of two intravenous infusions of allogeneic human bone marrow-derived mesenchymal stromal cells (allogenic-BM-MSC) and evaluate the potential efficacy of pre-transplant intravenous infusions of allogenic-BM-MSC to reduce the risk of acute rejection of corneal re-transplants.

As a Known Consignor, Biostór can ship cells without the use of X-ray scans. All air cargo and truck shipments are now subject to X-Ray scan. X-rays would be hazardous to the MSCs. Becoming “Known” involved Garda Vetting, the completion of a 1-day of Aviation Security Training course, writing a comprehensive Air Cargo Security Manual and SOPs, and a site audit by IAA.

Biostór’s Peadar MacGabhann comments, “Becoming a Known Consignor with the IAA was worth it and ensures that Biostór can support future VISICORT cell therapy trials and ensure the project reaches the conclusions that were planned at the outset. how this will impact the project.”

Feature image photo credit: Wellcome Collection with a Creative Commons 4.0 International license

VISICORT celebrates International Clinical Trials Day with the HRB-TMRN

EU funded projects VISICORT, ADIPOA-2AUTOSTEM and NEPHSTROM coordinated by the Regenerative Medicine Institute (REMEDI) at National University of Ireland, Galway exhibited at a unique outreach activity targeted at primary school students. The event called the START competition was the brainchild of the Health Research Board (Ireland)’s Trials Methodology Research Network (HRB-TMRN) in Galway. In celebration of International Clinical Trials Day and to draw attention to clinical research conducted in Ireland, young people were invited to design, conduct and report on a randomized clinical trial. On May 18, 2018, three of the short-listed schools assembled at the University in Galway to visit interactive exhibitions, talk with researchers, perform mini-experiments, take part in lively science demonstrations and collect their prizes. The winning school was St. Joseph’s National School from Kinvara, County Galway.

Special thanks to Dr Siobhan Gaughan who organized the stand, Georgina Shaw who prepared the stem cell plates and to NUI Galway volunteers Dr Tina Harte, Dr Cathal Ó Flatharta, Dr. Nahidul Islam, Hannah Egan, Niamh Leonard, Dr. Emily Growney Kalaf, Claire Dooley and Dulan Hasantha Jayasooriya who volunteered their time to work with the young people on behalf of the EU funded project, STEM promotion.  The STEMinator cards used at the exhibition were designed by Cúram, NUI Galway. Also thank you to Lauren, Alibhe and Charlotte for creating the stem cell models.

Read more about the START competition here.

VISICORT attracts attention at ARVO 2018, Honolulu

PI Dr Jesper Hjortdal (right) and Henrik Sejersen (left), Clinical Optometrist at the University Hospital Aarhus in Denmark presented VISICORT at the ARVO 2018 conference. The Association for Research in Vision and Ophthalmology (ARVO) meeting was held from 29 April – 3 May in Honolulu, Hawaii USA. This year’s theme was ‘Imaging in the Eye’. The VISICORT study was titled “Comparison of DMEK and DSAEK in high and low risk posterior lamellar keratoplasty”.

Jesper comments: “Our poster confirmed that on average, patients treated with DMEK obtain better visual acuity than patients treated with DSAEK, but that early re-operations are much more common. An interesting finding was that DMEK grafts had higher endothelial cell density after surgery than DSAEK grafts. In relation to high- and low-risk grafts, failures were similar in patients treated with DMEK/DSAEK.”
“The interest in the topic was very good, and many look very much forward to see results from the main focus of VISICORT: Immunological profiling of patients in keratoplasty.”

ARVO is the largest and most respected eye and vision research organization in the world. With nearly 12,000 researchers as members from over 75 countries, ARVO advances research worldwide into understanding the visual system and preventing, treating and curing its disorders. The poster session is very popular as many colleagues pass by and give comments.

 

VISICORT study published in Stem Cells

A VISICORT study was published recently in Stem Cells. The body of research entitled “Inter‐Species Incompatibilities Limit the Immunomodulatory Effect of Human Mesenchymal Stromal Cells in the Rat” by Paul Lohan, Oliver Treacy, Maurice Morcos, Ellen Donohoe, Yvonne O’Donoghue, Aideen E Ryan, Stephen J Elliman, Thomas Ritter and Matthew D Griffin was accepted for publication on 13 April 2018.

Abstract:

Mesenchymal stem/stromal cells (MSC) are an immunomodulatory cell population which are under pre‐clinical and clinical investigation for a number of inflammatory conditions including transplantation. In this study, a well‐established rat corneal transplantation model was used to test the ability of human MSC to prolong corneal allograft rejection‐free survival using a pre‐transplant intravenous infusion protocol previously shown to be efficacious with allogeneic rat MSC. Surprisingly, pre‐transplant administration of human MSC had no effect on corneal allograft survival. In vitro, human MSC failed to produce nitric oxide and upregulate IDO and, as a consequence, could not suppress rat T‐cell proliferation. Furthermore, human MSC were not activated by rat pro‐inflammatory cytokines. Thus, interspecies incompatibility in cytokine signalling leading to failure of MSC licensing may explain the lack of in vivo efficacy of human MSC in a rat tissue allotransplant model. Inter‐species incompatibilities should be taken into consideration when interpreting pre‐clinical data efficacy data in the context of translation to clinical trial.

VISICORT meets in Wexford, Ireland

The VISICORT consortium was hosted by Biostór Ireland in Wexford on April 26 – 27 2018 for a plenary meeting.

After work package updates were provided, the focus of the meeting became future plans for the remaining months of the project. Discussions focussed on the clinical trial timeline, the publication plans, the future of the VISICORT bio-bank, mechanisms to apply for funding to pursue additional studies, the biomarker analyses, and the “gold mine” of data sets and the potential for clinical and metabolomic studies.

Jesper Hjortdal presents human subject enrolment, follow-up and clinical data analysis.

Agenda VISICORT Wexford April 26 – 27

Prof Ritter presents VISICORT at Cornea and Ocular Surface Biology and Pathology conference

Prof Thomas Ritter, NUI Galway presented Dr Paul Lohan’s VISICORT findings at the Cornea and Ocular Surface Biology and Pathology meeting. The conference was held in Ventura, California from February 18-23 2018. The 2018 conference theme was ‘Defining the Mechanisms Through Which the Cornea, Tear Film and Immune System Operate Under Pathological Conditions’. Thomas’ presentation was titled “Mesenchymal stem cell therapies for efficient treatment of immune-mediated diseases of the eye”.

The Cornea and Ocular Surface Biology and Pathology conference programme can be found here.