Previous Fanconi Hope-Sponsored Research
2010-1018 Research
Read about the International Fanconi Anaemia Gene Therapy Working Group
2011 Research
Fanconi Hope awarded a grant of £20,000 to Dr Ketan J Patel, MD, PhD, from the Laboratory of Molecular Biology, Cambridge University towards his ongoing work on a research project entitled: Reconstituting and Dissecting Monoubiquitination in the FA Tumor Suppressor Pathway.
Dr Patel, who is recognised as a world expert in molecular research related to Fanconi Anaemia, was funded in this research programme by the US Fanconi Anaemia Research Fund (FARF). Fanconi Hope’s contribution to this funding represented a significant proportion of the total required over a year and demonstrated our commitment to support key FA researchers in the UK.
2010 Research
Fanconi Hope, in collaboration with the Fanconi Anemia Research Fund in the USA, helped fund this research project with a grant of August 2010 with a grant of £42,000.
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.
If successful, this project would help the research community:
• to understand specifically how FA mutations affect early haematopoietic development 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 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.