Fanconi Hope Funded Research
Fanconi Hope is pleased to announce that in collaboration with the US Fanconi Anemia Research Fund we have provided a grant of £30,000 for the first UK research programme relating to the use of stem cell technology in conjunction with gene therapy which may in future provide a cure for Fanconi Anaemia; ‘Using iPSC technology to understand early haematopoietic development in Fanconi Anaemia patients’. Fanconi Hope’s research grant of £30,000 is now funding the first phase of the work, and we have set ourselves a target of raising a further £100,000 for the remaining phases.
Background:
Recent joint research by the Salk Institute for Biological Studies in Calfornia, the Center of Regenerative Medicine in Barcelona (CMRB) and the CIEMAT Centre in Barcelona have shown for the first time that in principle human genetic diseases such as Fanconi Anaemia can be cured using a combination of gene therapy and induced pluripotent stem (iPS) cell technology.
The potential significance of this is that corrected cells from the patient’s own tissue would be used in a bone marrow transplant thereby avoiding the issue of tissue rejection which often causes cancers subsequently in transplanted patients.
This groundbreaking research has been shown to cure an FA-affected cell and in theory this could then be transplanted into a FA-affected patient to cure the blood-related element of the disease. However many hurdles remain before the theory can become practice not least in preventing the reprogrammed cells from inducing tumours, and the team are now funded to pursue research aimed at translating basic science into clinical cures.
Prof Majlinda Lako
Prof Chris Mathew
Now for the first time in the UK a collaborative research programme into this exciting new technology has been initiated between a group in Newcastle led by Prof Majlinda Lako working with induced pluripotent stem (iPS) cell technology and a group in London led by Prof Chris Mathew researching in Fanconi Anaemia.
Research Programme in Brief
In brief, the programme involves generating and characterising iPS cell lines (the first phase of the programme). Next, the team will study whether these iPS cell lines behave the same way as normal FA cells with respect to DNA repair, genomic instability and the ability to make blood cells. If they do, they will then have a good FA model (which can be used in a laboratory environment rather than testing on humans) to test different corrective measures/drugs for the faulty DNA repair mechanism. The team will then investigate to see whether the process of creation of blood producing cells is different for FA and control patients. This should give a better understanding of what goes on so that hopefully they can help improve the process of curing patients through new therapeutic regimes using gene therapy and iPS cell technology.
This research project is being funded by Fanconi Hope in collaboration with the Fanconi Anemia Research Fund (FARF) in the US. Fanconi Hope has provided a grant of £30,000 for the first phase of the work and has set a target to raise a further £100,000 for the remaining phases. This research topic was selected by the Trustees of Fanconi Hope from a shortlist of candidate UK research programmes which have been approved for funding by the FARF Scientific Advisory Board, whose 14 members comprise FA specialists from the US, Canada, Holland and the UK.
More Detailed Synopsis of the Research Programme:
Using iPSC Technology to Understand Early Haematopoietic Development in FA Patients
This is a collaborative study by Prof Majilinda Lako, PhD., Institute of Human Genetics, NE Stem Cell Institute, Newcastle University and Prof Christopher Mathew, PhD., Division of Medical and Molecular Genetics, Guys and St. Thomas Hospital, London to produce ‘induced pluripotent stem cells’ derived from patients with FANCA, FANCC, FANCG and FANCD2 to compare with cells derived from unaffected patients in order to understand better the role of FA genes in the development of blood-producing cells.
Fanconi Hope, in collaboration with the Fanconi Anemia Research Fund in the USA, has funded the initial tranche of this work through to August 2010 with a grant of £30,000, and we have set a fundraising target of £100,000 to fund the remainder of the programme.
If successful, this project would help the research community:
• to understand specifically how FA mutations affect early haematopoietic development (production of blood cells) in humans
• to work towards designing new therapeutic regimes by correcting the gene defect in human iPSC cells with the aim of using iPSC-derived haematopoietic progenitor cells for bone marrow transplantation in these patients
• to enhance the basic understanding of the role of DNA repair during the formation of blood cells.
Prof Majlinda Lako’s research group is focused on understanding of the basic biology of human embryonic stem cells (ESCs) and iPSC, their self-renewal and the efficient differentiation (conversion) of the human ESCs to haematopoietic lineages. The skills acquired during the course of recent studies (DNA repair and oxidative stress measurements) are of direct relevance to this proposal and are central to the successful execution of this project.
Prof Chris Mathew has considerable expertise in the identification of mutations in different types of FA and interactions of FA proteins with the breast cancer gene BRCA2 in DNA damage response He has also undertaken a large study investigating cancer incidence in relatives of FA in British families (575 individuals in total) and as a result of this has access to samples, from patients with different types of FA, some of which will be used for the derivation of iPSC lines.
Why is a new approach needed?
Previous research data suggest an important role for FA genes in haematopoietic stem cells (HSCs) and haematopoietic progenitor cell proliferation. Several mouse models have been created with the aim of modelling human FA behaviour. However, none of these models exhibit the haematological problems observed in FA patients. This necessitates the creation of human FA disease models which can be investigated.
A more attractive approach is the generation of induced pluripotent stem cell (IPSC) lines directly from the somatic tissues of disease patients. Pioneering work carried out in the last 4 years has shown that a set of transcription factors linked to pluripotency can directly reprogram human somatic cells to produce IPSC lines.
Derivation of iPSC from FA patients together with a robust differentiation method that has been established in Prof Lako’s group for producing haematopoietic progenitor cells from these could undoubtedly provide new insights into disease pathophysiology by permitting analysis in a human system, under controlled laboratory conditions.
Plan of investigation.
A. Generation and characterisation of iPSC lines from FA patients.
Because of the effort involved in derivation and characterisation of iPSC lines, the initial focus will be on making iPSC lines from 2 FANCA, 2 FANCG, 2 FANCC and 2 FANCD2 patients.
Expected outcome: The team intend to establish affected and control iPSC lines within 9-12 months.
B. Investigation of DNA damage response, radiosensitivity and genomic stability in control and FA patient derived iPSC lines.
It has been shown that cells lacking FANCD2, FANCC, FANCG and FANCA are more susceptible to DNA damage and to drugs that induce DNA interstrand cross-links. To investigate whether this occurs in iPSC lines derived from FA patients, various assays will be carried out in relation to:
• cell growth
• drug sensitivity
• radiation sensitivity
• DNA damage response
• Genomic stability
Expected outcome: This series of assays will determine if the radiosensitivity and genomic instability of the FA fibroblasts is retained by the iPSC generated from these cells. The team expect to complete this task within 12 -18 months.
C. Investigation of the haematopoietic differentiation of iPSC lines from unaffected controls and FA patients.
Deficiencies in any of the genes involved in the FA pathways impair haematopoietic stem cell expansion, but the effects of any of these genes during the ontogeny of haematopoiesis (alternative phrase required!) has not been addressed.
Expected outcome: This series of experiments will help determine whether early haematopoietic stem cell commitment and expansion is affected in FA patients. The team expect to accomplish this task within 12-18 months.
The importance of iPS cells and Gene Therapy for FA patients.
‘Induced’ pluripotent stem cells are a type of pluirpotent stem cell artificially derived from non-pluripotent cells. These pluripotent cells have the important ability to become almost any cell in the body and enable research to be carried out without the use of embryos.
Bone marrow failure resulting in the progressive decline in the numbers of functional haematopoietic stem cells is the most prominent feature of Fanconi Anaemia. The principle of gene therapy using iPS cells is that using skin cells from the FA patient, the defective gene in the patient’s cells can be corrected using gene therapy techniques. These repaired cells can then be reprogrammed into induced pluripotent stem (iPS) cells which can produce haematopoietic stem cell progenitors which then in turn produce healthy blood cells without risk of rejection, since the original cells are taken from the same FA patient.
Glossary of Stem Cell-Related Terms
