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Research

Research Update

After establishing the Captain Courageous Foundation 5 years ago and raising close to $2.5m our small family-run Foundation's mission to make a difference to children suffering Bone Marrow Failure Diseases might be coming a reality sooner than expected. For the last 2 years we have established and funded Australia’s first national collaborative research program (across 5 states) into these rare bone marrow failure diseases with the chance of offering some real hope to patients and family’s suffering these debilitating diseases. Remarkably, the research efforts have identified a suite of existing drugs that are already approved for use in humans for other diseases, that also have efficacy in treating experiment models of bone marrow failure and thus have the potential to be “repurposed” for the treatment in bone marrow failure syndromes in patients. As a result they are now possibly looking at patient clinical trials as soon as next year. This process from discovery to clinical trial can normally take close to 10 years and in excess of 100's of millions of dollars however the Captain Courageous Foundation might have some answers within 3-5 at a fraction of the cost. We are conducting a workshop at ANU in November this year with invited overseas collaborators to summarise the current research program and look at the path ahead. Critical funds are still needed to fund this next journey - every dollar counts.

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"Diamond-Blackfan Anaemia (DBA) is an extremely rare disease that affects the protein factories of the cell (ribosomes). Because these red blood cells cannot make enough protein to keep up with the high demand, they become ‘stressed’ – a process where these cells activate a self-destruct mechanism which kills them off and reduces the overall number of red blood cells in the body. Interestingly, this self-destruct mechanism is also an important cellular ‘brake’ that prevents blood cancer cells from growing. Unfortunately, there are limited treatment options for DBA patients at this current time. However, the medical research funded by the Captain Courageous Foundation has allowed us to make significant inroads into understanding the biology that causes DBA, with a view to finding new therapeutic strategies for the treatment of this disease.

Using world-class cutting edge technologies, we have mimicked the stress response that occurs in DBA and we have tested the impact of every gene in the human genome (about 18,000 genes) on this stress response. Excitingly, we have found a number of new targets that are able to reduce this stress in these cells and may lead to new treatments for DBA. Further to this, we have also tested a panel of just over 4000 drugs that are currently used in the clinic to treat other diseases, and we have found a number of these reduce the stress response in our DBA model. These drugs have the potential to be ‘repurposed’ to treat DBA patients in the immediate future. Remarkably, these same genes and drugs identified for the treatment of DBA also provide insights into to how to kill blood cancers and we are incorporating these findings into our cancer discovery program.

None of these studies would have been possible without the immense financial support of the CCF. We are confident that the findings from our studies will really make a difference to patients and families of patients with DBA and other similar types of diseases and lead to new treatments for cancer.”

Written by Dr Amee George, Peter Mac Cancer Centre - April 2015

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AUSTRALIAN DIAMOND BLACK-FAN ANAEMIA RESEARCH PROGRAM

Funded by the Captain Courageous Foundation

An Australian multi-centered approach to discover treatments for Diamond-Blackfan anemia and other rare bone marrow failure syndromes and to understand the mechanisms of action of novel drugs to treat blood cancers

What is Diamond-Blackfan Anaemia (DBA)? DBA is an extremely rare disease that usually develops in infancy and is characterised by low numbers of red blood cells and in many cases, by abnormalities of the face, head, upper limbs and heart. DBA patients are also predisposed to developing a number of different blood cancers, though it is not well understood why this occurs.

Treatments for DBA: Apart from bone marrow transplants, there is no cure for DBA. About 30% of children who suffer with DBA will respond to oral corticosteroids. However, long-term steroid medication inevitably leads to significant side effects (eg., brittle bones, suppressed adrenal gland hormone function, and increased risk of infection) and steroids may stop working at any time. Patients who don’t respond to steroid medication are faced with a lifetime of blood transfusions, which can lead to problems of iron overload and other medical complications.

Causes of DBA: Previous research has provided evidence that DBA is caused by mutations in or changes to genes that encode ribosomal proteins (RPs). Ribosomal proteins form part of a large molecular machine called the ribosome that is responsible for making all cell proteins. Each cell contains millions of ribosomes and the synthesis and correct functioning of ribosomes is critical for cells to be able to grow and survive. If a cell detects any change in the amount of these ribosomal proteins, it activates a process called nucleolar stress, which instructs the cell to stop growing or to self-destruct though a mechanism called programmed cell death (apoptosis). This is a problem for sufferers of DBA, because the mutations in ribosomal proteins preferentially affect the ability of patients to make sufficient numbers of red blood cells, which causes their anaemia. The exact reason why DBA preferentially affects the red blood cell precursors, even though the DBA causing mutations are found in every cell and tissue in the body, is not clear. Furthermore, it is not well understood at the molecular level why some carriers of the DBA mutations are unaffected, or conversely why some affected patients spontaneously undergo remission. DBA sufferers also have a significantly increased risk of developing blood cancer and other cancers during their lifetime.

A unique funding model to support research into DBA: The Captain Courageous (CC) Foundation has developed a unique approach to support medical research into the development of better treatments for DBA. Rather than supporting individual laboratories, they have brought together some of Australia’s most experienced scientists with knowledge in blood disorders, genetics and ribosomal proteins, to work as a Program. This program, named the Australian Diamond Blackfan Anaemia (ADBA) Program, has unified goals and a pipeline of interlinked research stretching from fundamental discovery to preclinical models of DBA.

Our research – new drugs to treat DBA and blood cancers: It is thought that mutations in ribosomal proteins that cause DBA do so because they induce a process called apoptosis in the red blood cell precursors leading to anaemia. A key gene that regulates the apoptotic cell death is a tumour suppressor protein called p53. This protein functions as a molecular switch and when activated, instructs cells to stop dividing or to die by apoptosis. The normal function of p53 is to prevent cancer by limiting the growth of abnormal cells. Thus, in DBA patients, we believe p53 is being activated in normal red blood cell precursors when it shouldn’t be. Our program of work is built on the central hypothesis that understanding the molecular mechanism(s) by which DBA-causing ribosomal protein mutations activate p53 leading to the death of pre-blood cells will allow us to identify new therapeutic targets and drugs for the treatment of patients with Diamond-Blackfan Anaemia. Understanding how RP mutations induce p53 will also facilitate the development of new approaches to treat blood cancers. This is because our program has already shown that interfering with ribosome synthesis to activate p53 and apoptosis is an effective mechanism to selectively kill blood cancers.

Specific Aims of the Research Program: Our program encompasses three stages of research: (i) discovery of therapeutic targets to treat DBA; (ii) validation of targets; and (iii) testing new therapies in preclinical models of DBA. In Stage (i), we are using state-of-the-art technologies and high throughput robotics platforms to perform ‘functional genomic’ screens of the entire human genome (which consists of approximately 18,000 different genes) to determine which genes, when either increased or decreased in amount, are important for the activation of p53 by DBA-causing mutations in RPs. In parallel, as an alternative strategy, we will test several libraries containing over 100,000 different types of chemical compounds, to determine whether any of these drugs and/or drug-like compounds can prevent the activation of p53 by DBA-causing mutations in RPs. The first library we test will consist of currently available small molecule drugs that are approved to treat human diseases to maximize the speed of moving promising hits into clinical trial. The identified genes or small molecules will represent possible targets to therapeutically treat DBA. In Stage (ii) of the program, we will validate that the lead genes and compounds from Stage (i) really do prevent or modulate p53 activation in human pre-erythrocyte cultures. Those genes and drugs that do will be progressed to Stage (iii). In Stage (iii), we will develop animal models that mimic human DBA, in particular the anaemia, and test our genes and drugs to identify those that can treat DBA in this system.

Research outcomes: The drugs and/or genes identified in this research program will represent potential novel targeted options for treating DBA patients to prevent or reduce the effects of their disease and give them a better quality of life.

Prepared by: George, Dr A. J., Hannan, Prof R. D., Pearson Prof R. P.


DBA International Consensus Conference Report Summary

Dr Amee George, Peter Mac Cancer Centre

In March 2014, a contingency of Australian DBA researchers, clinicians and members of the Captain Courageous Foundation attended the 13th DBA International Consensus Conference (ICC) in Atlanta, Georgia, organised and sponsored by the Diamond Blackfan Anemia Foundation (DBAF). The meeting bought together over one hundred of the world’s top experts at the forefront of DBA research and treatment.

Highlights of the conference included discussions about emerging therapies for the treatment of patients with DBA, with a number of potentially new treatment targets and therapeutic strategies identified. Adding to this is the data presented by our very own Professor Ross Hannan, a lead investigator in the Australian Diamond Blackfan Anaemia Research Program (funded by the Captain Courageous Foundation) that used a robotic approach to test every gene in the human genome to determine its role in the DBA response. Encouragingly his team has identified a suite of novel genes that prevent the DBA response from occurring. This data was well received from the audience and touted as a “breakthrough approach” in the identification of therapeutic targets for the treatment of DBA.

Another strong focus of the meeting was on the molecular basis of DBA. Evidence from a number of different research groups have identified a molecular process called ‘nucleolar stress’ and subsequent activation of a stress-response protein called p53 which may account for the failure of red blood cells to mature in DBA patients. Moreover, changes in the activity of the GATA1 gene is emerging as another solid candidate for DBA and DBA-like syndromes. Both of these areas are highly topical and are currently being investigated in further depth.

Overall, attendance at the conference was a highly beneficial experience, with much discussion and many research collaborations formed which will enhance our future investigation into the cause of and treatment for DBA. Many thanks must go to the DBAF for the invitation to attend and present at the conference.

 

Future Research

In line with our mission we will expand the Bone Marrow Failure research efforts, through further consultation with leading Australian academics and researchers, and sponsor additional projects that will speed up the research of Bone Marrow Failure Diseases and accelerate the path to a cure.

 

Intellectual Property and Collaboration

Captain Courageous will seek to protect any discoveries resulting from its funded research and to reinvest any commercial benefits into its research objectives. Notwithstanding this, it is intended that Captain Courageous will share its research outcomes with the DBA Foundation and the Daniella Maria Arturi Foundation in the USA and like organizations focused on research into bone marrow failure diseases.

In order to expand the knowledge and network of our project, we sponsored the team at Hanson to attend the ASH conference (American Society of Haematology) in San Diageo, in December 2011. This is one of the largest haematological conferences worldwide, and this year, there was a particular focus on Bone Marrow Failure and DBA. DBA currently seems to be at the forefront of research within the haematological field as they find new links to other diseases.

 

Captain Courageous Foundation Research Workshop

On Aug 7th 2013 we hosted out first strategic workshop at Mount Lofty House. Facilitated by Simon Starr from DNA3 who kindly donated his services not only for the workshop but for the pre work up as well. We were lucky enough that one of our board members, Rachel Atkins, was able to attend along with Jeff, Bill and myself. Please read Ra’s comments below on the workshop and what she believes Captain Courageous can do.

“It’s not often that I am lucky enough to sit in a room all day surrounded by professors, researchers and scientists. Yes, I did say lucky. This is because I was attending the Captain Courageous Foundation Research Workshop. Jess and Jeff Bond had rallied together an impressive line up of Australia’s leading professionals in the field of Bone Marrow Failure to collaborate.

This is unique in several ways. It’s very rare in Australia and around the world for that matter for researches to get together in one place and share ideas. The nature of their business (sadly) leans them to protect their intellectual property, patents, and findings. In this instance 12 inspiring researchers, Ribosomal Professors, Sarcoma researchers, Clinicians…people with serious clout, the best of the best, sat around a table and talked. They shared their research, methods, goals, results and ambitions in a truly collaborative environment with the main aim to make a difference.

This coming together of minds will hopefully be formalised – this is even rarer – to create a national singular research project into Bone Marrow Failure diseases including DBA from which Angus Bond suffers. The workshop group and facilitator Simon Starr have strategically put together a working model for research which includes, aims, objectives, strategies, time frames and funding requirements to guarantee an acceleration of the research which in turn may find a cure for these diseases.

The primary goal of the research is to produce either a drug treatment for these patients to give them better treatment options or pottentially a cure. More importantly these would be drugs that could also treat blood cancers at a very early stage.

So I now know that diseases such as DBA come about when a gene mutates it causes a stress response from the cell which causes the symptoms that patients feel. But what I know best, is that there is a good chance that the Captain Courageous Foundation can truly make a difference because it is the rare diseases that can sometimes hold all the answers.” Rachel Atkins

Thank you to Ra, Simon and our team of Researchers for a fantastic day and planned research future.

Research news

See the latest DBA research news by viewing this website: www.dbafoundation.org