UK & Ireland Fanconi Anaemia Family/Clinical Network

 Research just published in Nature Structural and Molecular Biology by Dr Helen Walden of Cancer Research UK (and a member of our UK FA Research Network) describes how her team have unravelled the structure of the FancL protein.
Dr Walden says “We have taken the first full atomic snapshot of a protein in this cell repair pathway, right at the very heart of the route by which cancer cells defend themselves against treatments which are intended to destroy them. By blocking this repair ‘ignition switch’, it may be possible to boost traditional treatments. As such, it’s a drug target.”

This link between FA and potential mainstream cancer cures amply illustrates the importance of spending money on research into orphan diseases such as FA. This is clearly recognised by Cancer Research UK as they have over 7 people  in 2 separate research labs currently working on FA. 

More: http://news.scotsman.com/science/New-hope-as-cancers39-.6071258.jp

The Ethics and Law Advisory Committee (ELAC) have now considered the outcomes of the consultation event and have made recommendations to the Authority for the future licensing of preimplantation tissue typing.  In summary,  ELAC have recommended that for preimplantation tissue typing a case-by-case approach should be maintained for the immediate future, that there should be a commitment to further a further reduction in the time taken to make decisions, and that a greater range of information should be made available on the HFEA website for people seeking this kind of treatment.
 
The Authority considered the recommendations of ELAC on 20th January and key decisions will be published on the HFEA website shortly.  
The ELAC papers and the minutes of the discussion had by the Committee can be found here:  http://www.hfea.gov.uk/5669.html
The Authority papers are now published , and can be found here: http://www.hfea.gov.uk/5721.html

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 international 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.

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 of raising 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.

Further details of the research can be found on the Fanconi Hope Funded Research page.

An HFEA Consultative Meeting was held on 1st Dec 2009 to review the licensing conditions for PGD for later onset, lower penetrance conditions and for HLA tissue typing. See Agenda and Discussion document – case by case approach to PGD

The meeting was attended by around 50 people with speakers for and against change. Attendees with an interest in FA included Dr Josu de la Fuente from St Mary’s Hospital, London, Colleen Lynch from Genesis Genetics and Bob Dalgleish from Fanconi Hope. This post is written by Bob Dalgleish.

An introduction from Juliet Tizzard, HFEA Head of Policy was followed by presentations from:-

- Dr Sue Price, HFEA Authority Member
- Dr Sioban Sengupta, UCL Centre for PGD
- Dr David King, Human Genetics Alert

Presentation material from the first two speakers is available on request. (Dr David King spoke without supporting material).

2 Consultation workshops were then run in parallel:-

Workshop A. Case-by-case licensing of lower penetrance, later onset conditions. (No Fanconi Hope representation)
A workshop in which participants were asked for their experience of the
case by case licensing process lower penetrance, later onset conditions
and consulted on alternative models for the future.
 
Workshop B. Case-by-case licensing of tissue typing applications. (Attended by Bob Dalgleish from Fanconi Hope)
A workshop in which participants were asked for their experience of the
case by case licensing process for preimplantation tissue typing and
consulted on alternative models for the future.

In Workshop B three options were presented for discussion, namely;

Option 1. Status quo: Continue to license applications on a case by case basis. The Licence Committee
would continue to be responsible for licensing novel conditions, and the ELP responsible for
licensing applications from subsequent families, on the basis of evidence provided from the
clinician responsible for the sibling’s care. This delegation of subsequent decisions to the ELP
may help to resolve concerns about the time the process takes.

Option 2. Centres to notify the HFEA of the intention to tissue type. The Licence Committee would
continue to licence novel conditions. Clinicians would assess the appropriateness of treatment in
particular family cases, using HFEA Code of Practice guidance. Centres would simply notify the
HFEA that they intended to tissue type, by supplying to the HFEA a letter indicating the support
of the sibling’s treating clinician.

Option 3. Cease consideration on a case by case basis. The Licence Committee would continue to license
novel conditions. The clinician would have responsibility for deciding the appropriateness of
treatment in particular cases, using HFEA Code of Practice guidance. The HFEA would require
clinics to obtain the support of the sibling’s treating clinician, as currently set out in the case by
case application form. Evidence of this support and adherence to Code of Practice Guidance
could be checked on inspection.
It was clear that few could see the logic or benefit of case-by-case applications as the application forms per family were ‘largely cut and paste’ according to the London PGD/HLA/IVF provider so the decision was not actually being made on a per family basis in any case. The HFEA were also unable to say whether for any two families with the same condition different decisions had been made.  It was seen that the patient’s clinician was in the best position to judge the appropriateness of PGD/HLA/IVF and those clinicians were already working within a framework of HFEA guidelines so the checks and balances were still there. This view came from across the spectrum of clinicians, both PGD/HLA/IVF providers and support groups.

Of the 3 options, out of around 18 participants I believe 17 voted for Option 3, with only Dr David King dissenting.
The forum was advised by the HFEA that taking position 3 required acceptance of the fact that the HFEA could review the position in the light of new evidence such as embryo damage during cell selection.

Plenary Session Summary
Danny Edwards summarised the Tissue Typing Applications Workshop View in the Plenary Session as follows.
There was a very strong view that HLA tissue typing should be brought into line with PGD, and in fact there is an even stronger justification for this than for cancer predisposition. This would mean a move away from case-by-case approval removing one of the main uncertainties for families, who already have to deal with the uncertainties of funding, in particular as some funding bodies will not consider funding until the HFEA have licensed the case of a particular family.
This will require a Framework of Guidance which will define for which conditions HLA will always be the best treatment.
There was a call for more research on cure rates as there is a lack of information for families on the efficacy of the treatment.

The summary on Licensing of Lower Penetrance, Later Onset Conditions was that this had to be considered on a condition by condition basis as to whether it should be agreed on a case-by-case basis

Next Steps
The recommendations will be taken to the Ethics and Law committee on 15th Dec with subsequent recommendations to the HFEA in January 2010.

We are delighted to welcome Dr Helen Walden from the Protein Function Research Laboratory at the London Research Institute in Lincoln’s Inn Fields to the UK FA Research Network. See Research Network list for further details.

Her lab is a structural biology lab dedicated to understanding protein regulation through ubiquitination, and they have recently determined the full-length atomic structure of FANCL.  This has been accepted for publication and should be out shortly. The whole lab is now working towards structurally and functionally characterising the core complex and the ubiquitination of FANCD2 and FANCI.

She is intending to organise a one-day meeting/get-together of many of the UK-based FA researchers in spring 2010 in the hope of stimulating some collaborative efforts.

Dr. Spencer J. Collis has become a member of the UK FA Research Network
Dr Collis has worked in Fanconi Anaemia research for several years and has recently moved to Sheffield’s Institute for Cancer studies to set up his own lab. His research will focus on the identification and characterisation of novel genome maintenance factors and how these relate to genetically unstable human diseases such as cancer, Seckel syndrome and Fanconi Anaemia.

Contact details

UK and Ireland Fanconi Anaemia Clinicians/Family Meeting.

The first UK and Irish FA combined family and clinicians meeting, organised by Fanconi Hope was held in the grounds of Chatsworth House, the ancestral home of our patron, the Duchess of Devonshire. The first day’s meeting was held in the farmyard/ adventure playground, which was perfect for entertaining the children and provided an informal setting for the meeting.

16 families from all over the British Isles attended and the patients ranged in age from 3 to 23. A number of UK Clinicians with an interest in FA attended, as well as invited speakers from Germany Spain and the UK. It was wonderful to have the opportunity for family members to talk to these interested professionals over a cup of tea. We also welcomed Marie Pierre and Christophe Bichet and Ralf Dietrich, representing the French and German FA Family Groups respectively. In total around 60 specialists, parents and children attended.

Workshops were set up throughout the room where families were then given the opportunity to talk to nutritionists or have help in interpreting some of the medical terms and jargon that relate to the condition. In addition a representative from the charity Contact-a-Family was there to offer advice on who to contact regarding the practical difficulties of having an ill child and information on the range of counselling services.

An impressive line-up of speakers followed a buffet lunch. Dr. Beki James (Genetics and Epidemiology unit, University of York) discussed the progress being made in the U.K. towards a registry of all UK Fanconi patients, (the UKIFAR). She explained the importance of this in facilitating future research as well as maintaining consistent standards of care across the UK.

Dr. Holger Tönnies (Institut fur Humangenetik, Universitatsklinikum Schleswig-Holsten, Kiel, Germany) explained in detail the progress being made in the chromosomal analysis of blood and bone marrow and discussed its usefulness to clinicians and advantages to patients.

Ms. Evelyn Ward (Paediatric Dietician, St. James’ Hospital, Leeds) gave details of the dietary difficulties Fanconi patients experience along with some practical advice. An interesting discussion took place with a complementary medicine nutritionist on the possible advantages of using dietary supplements.

The last speaker of the afternoon was Dr. Juan Beuren (Hematopoiesis and Gene Therapy Division, CIEMAT, Madrid Spain) He gave us a fascinating insight into the current gene therapy research as applied to FA and discussed future possibilities.

Meanwhile, the children and a few adults enjoyed the animal handling session- and no doubt in those families the demand for guinea pigs in all households will have increased. Later they enjoyed a bumpy ride on a tractor and trailer around the estate where the saw deer and some of the beautiful sculptures that adorn the extensive grounds.  The children were given the chance to try milking which was “very hard”. When they decided on a change of scene they had a chance to explore the exciting adventure playground and play in the huge sandpit.

After a short break the meeting reconvened in a local award winning restaurant. The cheerful staff didn’t seem to mind small children running around or the art workshop set up to amuse the children. The last presentation of the day was given by Prof. Adrian Thrasher (Paediatric Immunologist, Great Ormond Street, London). He gave families and clinicians an insight into the challenges in setting up and participating in gene therapy trials.

The following day an informal meeting was held to discuss the previous day’s events, to reflect upon the progress the charity has made in its first year and consider future plans. The meeting ended with an inspirational talk from Paul Carruthers, an FA supporter who had just completed a cycle ride from Lands End to John O’Groats, a distance of almost 900 miles, raising a magnificent £2000 for the Fanconi Hope Charity.

We were also able to offer FA patients the chance to take part in a research programme screening for mouth cancer run by Eunike Velleuer with the help of Ralf Dietrich.

We received lots of positive feedback from both families and clinician and the general consensus was that it was a huge success.

And finally a selection of quotes from the feedback forms received:

“Overall, very informative.”

“It gave me enthusiasm and hope in the future for FA sufferers.”

“Good to have a balance of serious informative events and relaxing chat.”

“Great venue for kids, and the people all mixed well.”

“Ideal venue to keep the kids entertained and a million miles away from having them endure another hospital visit in order for us to find out more”

Several new information sheets are now available.

For Families:

An information sheet on Head and Neck Cancers by Thomas Carroll, and a sheet on Advice on Nutritional Problems for patients with FA prepared by Ms Evelyn Ward, Paediatric Dietician, St James’ Hospital, Leeds.

For Clinicians:

A guidance document for children’s hand surgeons concerning congenital hand anomalies in Fanconi Anaemia has been prepared by by Ms Grainne Bourke, Consultant Plastic Surgeon, Leeds General Infirmary.

A guide to Nutritional Management of Patients with Fanconi Anaemia has been prepared by Evelyn Ward, Paediatric Dietitian, St James’s University Hospital, Leeds.

The US Guidelines for Diagnosis and Management of Fanconi Anemia , 3rd Edition, published by FARF is now available and can be downloaded here

One recent stem cell science development that has future clinical relevance for the gene therapy of FA-affected individuals is induced pluripotent stem cell (iPS) technology. This iPS technology means that haematopoietic stem cells can be generated from cells from other tissues, e.g., skin, and is not dependent on the presence of viable haematopoietic stem cells in the bone marrow. Further information concerning this development can be found here.

You can also listen to a ‘Podcast’ on the topic by the online journal Nature.(Click on ‘Play’ next to Reprogramming diseased cells topic on the LHS of the page.)

One of the key researchers involved in this field is Dr Juan Bueren. You will have the opportunity to meet him and hear him speak on this topic at our Clinicians/Family meeting at Chatsworth House on Sept 18th 2009