sohanaresearchfund.org

NEW PROJECTS

Stem Cell Regeneration of the Ocular Surface in Recessive Dystrophic Epidermolysis Bullosa

Aiming to establish a high-quality preclinical platform for therapy of corneal disease in people with RDEB. Goal is to develop a three-dimensional (3D) cornea with ABCB5-expressing limbal stem cells derived from induced pluripotent stem cells in which the RDEB-causing mutations in the type VII collagen gene have been gene edited using the CRISPR/Cas9 system.

START DATE 1 JULY 2016.   2YEAR DURATION   $250,000 per year

Gene Editing

Project agreements are in progress regarding a next generation genome sequencing project with a view to clinical trials within a 3-5 year framework.

We are pushing forward research here in the UK and at leading centres in the US. The aim is to get to a proof of concept clinical trial within five years, on both sides of the Atlantic and as fast as the regulatory authorities will allow. More details to follow. This work will not just benefit EB but will in theory be applicable to the people who suffer one of the 5,400 Genetic Disorders in the world, which accounts for 10% of people, 30 million in Europe alone.

BBC Health Report 1 Dec 2015 http://www.bbc.co.uk/news/health-34972920.

The UK team at Great Ormond Street and the Institute of Child Health has a world first in using TALENS to cure a baby with Leukaemia.

Reported on BBC Health http://www.bbc.co.uk/news/health-34731498.

New article in nature.com 8 Dec 2016 CRISPR/Cas9-based genetic correction for Recessive Dystrophic Epidermolysis Bullosa. http://www.nature.com/articles/npjregenmed201614.

Planned to follow Lenticol F   – Gene Therapy Lenticol M Work packages 2 and 3

To follow on from Lenticol F, providing proof of concept for intravenous gene modified cells and an associated clinical trial.

ESTIMATED £1.5 MILLION. We are holding funding towards this trial.

COSTS ASSOCIATED WITH THE WORK:

Batch of vector £450K

Generate patient MSCs £300K

Run a trial to test Lenticol M £750K

Appoint a project manager, post doc and trial coordinator £450k

ONGOING PROJECTS

CELL THERAPY

ADSTEM Clinical trial

Professor John McGrath, Kings College London. Guy’s and St Thomas’s NHS Trust.

£432,000 FUNDING FROM SOHANA RESEARCH FUND

A follow up study in adults understanding how allogeneic Mesenchymal Stromal Cells given intravenously can modify disease severity in Recessive Dystrophic Epidermolysis Bullosa. There will be ten patients on this trial and the first patient injections have been given. The main objectives of this study is:

1 to assess the clinical responses in adults with RDEB receiving intravenous MSCs.

2 to identify the best cohort of individuals to target for future trials and therapies.

3 to improve understanding responsiveness to MSCs.

4 to identify candidate molecules necessary to activating MSCs and make them clinically more potent.

5 to assess its impact on reducing disease.

This is a prospective, non-randomised, open label study. All study participants will receive two intravenous MSC infusions at baseline Day 0 and Day 14 and will be followed up for a 12 month period following the first infusion. Each subject will undergo an initial screening including physical examination, assessment of vital signs and disease severity assessment.

START DATE JULY 2015. 2YR DURATION

UPDATE: The trial has ended and sample analyses and monitoring has begun.

GENE THERAPY

Lenticol F Clinical Trial – Lentiviral-mediated COL7A1 gene-modified cell therapy for RDEB. Institute of Child Health, Guildford Street London. 

Dr Waseem Qasim, Prof Adrian Thrasher and Prof John McGrath. Institute of Child Health, Guildford Street London.

THE COST OF THIS TRIAL IS £499,320 FROM THE SOHANA RESEARCH FUND (PRECLINICAL WORK WAS FUNDED BY DEBRA AUSTRIA €500,000)

The group have developed a Lentiviral vector which encodes a collagen VII gene, modified to reduce the likelihood of instability of the gene and have now produced gene-corrected fibroblasts under clinical good manufacturing process (GMP) conditions. Ethics and MHRA have given regulatory approvals and the clinical trial, LENTICOL-F (A prospective phase I study of lentiviral-mediated COL7A1 gene-corrected autologous fibroblast therapy in adults with recessive dystrophic epidermolysis bullosa) started last year.

This study proposes to take skin samples from 6-10 adults with RDEB to produce “person-specific” gene-corrected fibroblasts. When sufficient cells have been grown, they will be injected back into the donor’s skin. Three injections will be given 1-2 millimetres under the skin surface, covering an area about the size of a once pence piece. Blood analyses and skin biopsies will be performed at various time points as per the monitoring schedule over 12 months. The primary objective is to evaluate safety, but also to allow analyses of type VII Collagen expression and anchoring fibrils in the injected skin and assess immune response to newly expressed collagen VII. The first patient was injected with the fibroblasts on 30/11/2015 and we await results of this ground breaking work, which is a world first in this condition.

RESEARCH STARTED 2012

CLINICAL TRIAL START DATE OCT 2015. 2 YEAR DURATION

ONGOING

Limbal Stem Cells for treatment of corneal wounds in Epidermolysis Bullosa

Professor Jakub Tolar Professor of Paediatrics, University of Minnesota.

PROJECT COMMISSIONED BY THE SOHANA RESEARCH FUND. $250,000 TOWARDS THE FIRST YEAR OF THE PROJECT FROM SOHANA RESEARCH FUND

Most people with RDEB experience corneal erosion, an exquisitely painful condition that causes loss of corneal clarity and compromises clear vision. The aim is to combine cutting-edge gene correction and Limbal stem cell technologies to fill this therapeutic gap and realize the potential of individualized, targeted, genomic-medicine based cellular therapy for RDEB. This is the first project in the world trying to address the problems associated with RDEB eyes. STARTED 2014

SRF has committed to a further 2 years of funding for this work ($250,000 per year for two years) has begun.

Gene Therapy Lenticol-M Work package 1

COST OF PROJECT £467,185 FROM THE SOHANA RESEARCH FUND

Mesenchymal Stromal Cells engineered to express collagen VII for the treatment of Recessive Dystrophic Epidermolysis Bullosa. The expectation is that patient derived gene modified cells will have a longer lasting effect than donor MSCs.

Pre Clinical proof of concept. This project follows on from Lenticol F and aims to provide an intravenous treatment for RDEB.

UPDATE: This project is ongoing, we expect a detailed update in Jan 2017, where evaluations will be made regarding progress to clinical trials.

Work package 2 and 3 to follow.

RDEB SCC Exome Sequencing

Lay summary extract from the full application submitted to SRF.

Dr Andrew South, Thomas Jefferson University USA.

Dr Raymond Cho University of California USA.

PROJECT COMMISSIONED BY THE SOHANA RESEARCH FUND. $250,000 TOWARDS THE FIRST YEAR OF THE PROJECT FROM SOHANA RESEARCH FUND

UPDATE: Our sequencing study of mutations that arise in RDEB cancer has provided us with tremendous insight into how these terrible cancers develop. Our work shows that RDEB cancers are more similar, in many ways, to cancers in the general public which arise in the mouth, rather than those cancers that arise in the skin and which are caused by UV light. This observation may open new horizons to explain why RDEB cancers are very aggressive, because mortality rates in the general public are higher for cancers of the mouth compared with similar skin cancers. We’ve also discovered that mutation processes associated with microbial infection are enhanced in RDEB cancer which may lead to new ideas for cancer prevention. Finally, our data show that a number of pathways which can be targeted with new therapies are activated in RDEB cancer, and this study now provides rationale for pursuing these targets for therapy development. We are very grateful to the Sohana Research Fund for supporting this important study of RDEB cancer, which we believe has been extremely successful. We are now in the process of submitting the results of this study for scientific publication.

 

COMPLETED

EBSTEM Phase 1/11 Clinical Trial of Mesenchymal Stromal Cells in RDEB

Professor John McGrath, Kings College London with Great Ormond Street Hospital for Children NHS Trust (London) and collaborating with Utrecht, Netherlands.

FUNDING FROM GOLDMAN SACHS GIVES VIA SOHANA RESEARCH FUND £450,000.

PROJECT OVERVIEW: This was the first UK trial aiming to lead to a treatment for children with RDEB. It seeks to establish if MSCs from unrelated donors who do not have EB can benefit children with RDEB in a safe efficacious way. It led to reduced skin inflammation, blistering and better wound healing. This trial may be extended to use matched cells either cord or matched donor cells to see if there are further benefits of introducing cells that have a compatible tissue match. GOSH transplant surgeon Dr Paul Veys is overseeing BM transplant possibilities.

The EBSTEM Trial was the subject of a BBC Health news report in Nov 2013.

STARTED JULY 2013. 2 YEAR DURATION (reduced to 1 year)

COMPLETED

The EBSTEM results have now been published in the Journal of Investigative Dermatology 23 April 2015 under the title “Potential of Systemic Allogeneic Mesenchymal Stromal Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa”. JInvest Dermatol dol:10.1038/jid.2015.158; accepted article preview online April 23, 2015.

UPDATE: The use of MSC cells for clinical care is being discussed.

A TALEN based approach to developing safer, more effective treatments for people with EB.  Dr Jakub Tolar, University of Minnesota, USA.  Funding  from Sohana Research Fund

Project overview

The goal of this project is to develop safer, more effective, individualised treatment options for children with EB, building on experience gained from the first clinical trial of a bone marrow transplant (BMT) for children with severe EB (RDEB and JEB), at the University of Minnesota. While this experimental BMT procedure was the first systemic (whole-body) treatment option for EB, the unwanted side effects make the development of safer options essential.

The aim of the project is to develop a treatment based on a patient’s own cells, corrected in the laboratory for the gene defect, and returned to the EB individual: the advantages of this approach would be absence of the severe potential side effects associated with the BMT procedure, and the problems of rejection of cells from unrelated donors. To date, such approaches have been hindered by difficulties in tailoring gene correction strategies for a unique patient mutation as well as in producing patient-derived cells that are suitable for transplant.

This project will combine two technologies, iPSC (induced pluripotent stem cells) and TALEN (transcription activator-like effector nuclease), aiming to develop a safer, more effective, treatment.

Detailed Aims
The research group has already developed keratinocyte and fibroblast cell lines from approximately 20 people with RDEB, and has the technical expertise to generate induced pluripotent stem cells (iPSC) from EB skin cells. By correcting iPSC derived from individual patients, the aim is to avoid the immune reaction which can occur with transplanted cells from unrelated donors.

The aim is to correct the faulty RDEB gene in iPSC by a ‘gene-editing’ approach, whereby the gene is edited back to the correct normal sequence without disrupting the surrounding DNA. This will be achieved using transcription activator–like effector nucleases (TALENs), engineered proteins which function as molecular scissors which cut the DNA precisely, allowing introduction of the normal sequence, thus resulting in permanent correction of the mutation. Preliminary results using RDEB patient-derived cells show that it is possible to use TALENs to mediate a permanent gene repair in such cells in the laboratory.

Following TALEN candidate selection we will pursue a gene correction strategy in tandem in both fibroblasts, and iPSC derived from patient cells to maximize the likelihood of success in developing therapies tailored for individual EB patients. We will use iPSC to generate cells that will allow us to model both disease development and correction both in cells grown in the lab, and in EB animal models.

Within the timeframe of this grant, we aim to provide proof of principle for the feasibility of a truly individualised, genomics-based medicine approach for the treatment of EB. 

Help us, to help children and adults suffering the excruciating pain of EB. 100% of your donations to the Sohana Research Fund go towards this groundbreaking research

Thank you

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