About The Stop ALD Foundation
The Stop ALD Foundation focuses on accelerating the process of developing new knowledge and new therapies for adrenoleukodystrophy (ALD), and works to accelerate implementation of newborn screening for ALD. As well, there is a focus on the adult form of the disease, Adrenomyeloneuropathy (AMN). We also educate the medical profession and the public about ALD/AMN, raising awareness in order to improve detection, diagnosis and treatment. In addition, we serve as a resource to families affected by the condition.
Our mission is threefold: Prevention, Diagnosis & Cure
Many cases of Adrenoleukodystrophy could be prevented by increased awareness of the fundamental facts about this often-lethal genetic disease.
Thanks to years of scientific research, the ALD defect can be identified in testing, either by screening women prior to becoming pregnant for carrier status or by conducting specific prenatal testing during pregnancy.
For example: Imagine a young woman who undergoes genetic counseling as she is planning to try to conceive a child. Although she has no history of genetic disease, a thorough family history reveals that she has a great-uncle who has difficulty walking. Although further investigation reveals no other family medical issues, given the particular genetic inheritance patterns and differing clinical signs of ALD, this woman should be screened for ALD carrier status.
Many families who are experiencing the devastating effects of this disease have a similar spotty suspicious medical history.
Carrier status screening is currently performed on blood samples and can be done for under $200 within 2 weeks. However, this test does have a very low false negative rate. To do a definitive DNA test requires 4-6 weeks and costs between $329 and $1200, depending upon whether the family mutation is already known. For more information, contact the Kennedy Krieger Institute.
Expanding carrier screening and prenatal screening through a concerted, targeted approach aimed at educating the healthcare profession could yield dramatic results within two years. In particular, genetic counselors must be educated about probing for these seemingly obscure details in sometimes distant family medical history. The Stop ALD Foundation's Prevention mission aims to use existing professional organizations for these specialists to disseminate key information about this approach to screening. Scientists at Johns Hopkins University have recently developed an experimental blood test for ALD, and the Mayo Clinic is preparing a study to find out if the test can effectively be used to screen newborns. (However, once the screening test is validated, that only means that it will be available; it may not necessarily be required as part of standard newborn screening.)
Heightening awareness of ALD among the general public requires a somewhat different approach. The Foundation intends on consulting with organizations such as the AMA, the Surgeon General, pharmaceutical companies, and others for guidance towards the most rapid, effective, and economically feasible strategies to heighten awareness. We have distributed Avoiding the Misdiagnosis of ALD, a comprehensive report detailing the medical presentation of ALD along with information regarding diagnosis, common misdiagnosis, treatment and prognosis, to more than 15,000 physicians throughout the U.S., with a special focus on pediatricians.
All currently accepted diagnostic techniques for ALD have proven their effectiveness. Unfortunately, these accurate tests are often not even considered until late in the course of the disease. The Foundation's mission in this area, therefore, is the prevention of misdiagnosis.
Initially, ALD-afflicted boys are typically misdiagnosed with attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD), behavior problems, socialization issues, and related conditions. They are often prescribed drugs, such as Ritalin, that are intended to alter their behavior. They may also be referred to various therapists. Years may pass as their disease worsens.
For many medical conditions, a delay in reaching the accurate diagnosis is unfortunate, but not necessarily a matter of life and death. This is not the case with ALD. Late diagnosis of this disease is often akin to a death sentence. Many young boys, instead of playing Little League, scoring soccer goals, and camping out with friends, are in graves. If the disease is diagnosed early enough, these boys may have a chance to survive.
As with the Stop ALD Foundation's Prevention Mission, the key here is awareness and education. Parents, teachers, principals, psychologists, psychiatrists, pediatricians, therapists, and others should be aware of ALD as a possibility when young boys have learning, concentration, and social problems -- particularly when these issues do not respond to initial therapy.
To attain the goal of speedy and accurate diagnosis, The Stop ALD Foundation is committed to raising the awareness and knowledge of the above people. Before a child is referred to a therapeutic school, and labeled with disorders such as ADD, ADHD, autism, and Asperger's Syndrome, a simple, non-invasive brain MRI should be performed. Any boy or man who is diagnosed with adrenal insufficiency should also be tested for ALD.
How The Stop ALD Foundation is Helping to Find a Cure
Like a venture capital firm, we seek out creative, promising ideas and support them with whatever resources are necessary to bring the project to successful completion. But instead of seeking out ideas that can make a lot of money, we pursue therapy ideas with the greatest promise of curing ALD and Adrenomyeloneuropathy (AMN) .
The Stop ALD Foundation fills the gap between research, where new scientific ideas are discovered, and development, the delivery of a new therapy to human patients. Ordinarily, this gap -- known as translational research -- is filled by pharmaceutical or biotechnology companies, but with less common conditions, such as ALD and AMN, it isn't profitable for them to do so. That's where the Foundation comes in.
The Stop ALD Foundation's Two Main Research Goals
We work with innovative, forward-thinking ALD and AMN researchers on two main goals:
Goal 1 -- Target: Seek out therapy targets as new research and treatment techniques become available
Analyze latest findings and technologies
Identify possible methods of intervention
Refine with ALD/AMN and therapy development experts the potential of each idea
Define the therapeutic to be developed
Goal 2 -- Develop: Manage the development of therapies on an aggressive timetable
Validate the therapeutic through experimentation
Design and implement safety studies
Specify and manage the manufacturing process
Initiate the filing of an Investigational New Drug application with the FDA and other regulatory agencies.
Plan and enable human trials in collaboration with leading ALD and AMN research centers
The work defined above is generally performed by biotechnology and pharmaceutical companies, but in Orphan Diseases, such as ALD/AMN, it is left undone. We are stepping in to fill the gap between research, where ideas are discovered, and development, the delivery of a therapy to human patients.
Our guiding principle is to make the investments that will most effectively lead to viable therapies in the shortest time frame. We do not accept grant applications; instead, we select and manage projects initiated through the foundation staff's contact network of ALD/AMN and disease therapy experts. This allows us to act rapidly to pursue promising ideas.
Gene therapy research and implementation as a treatment for ALD and AMN have been the highest priority since the inception of The Stop ALD Foundation. In the early days of The Stop ALD Foundation, a thorough review by ALD experts, along with an international multi-disciplinary team, concluded that gene therapy applied to the patient's own stem cells was the best approach to pursue.
After comprehensive preclinical lab experiments, including work in tissues and cell cultures and in rodents, yielded encouraging results, a new gene therapy vector was designed, and ultimately manufactured by a California-based biotech company.
The objective of the initial trial was to test both the safety of this new approach, as well its effectiveness. Usually, in an initial trial such as this, the regulatory bodies such as the US Food and Drug Administration or France's AFSSAPS (their equivalent of the FDA) will only allow initial testing of safety, to make sure the therapy does no harm. However, since ALD is a rare disease, the trial will also be allowed to study how effective the treatment is as well. This is both unusual and wonderful news since the research team can learn more from the initial trial.
From a disease perspective, the boys in the trial are considered good candidates for stem cell transplant (relatively earlier stages of cerebral ALD), but do not have good matches available. These boys would otherwise have to wait for a match to become available -- all the time getting sicker and sicker, or they might possibly be transplanted with a significantly mismatched donor and need to face the sometimes fatal results of this type of procedure.
The first clinical trial of the gene therapy approach took place in France, under the supervision of Patrick Aubourg, professor of pediatrics at Hospital St. Vincent in Paris. Four boys were treated, and the results of the first two that were treated were reported in a landmark paper in Science November 2009.
The ALD gene therapy project was a multimillion dollar protocol. The Foundation was successful in spending only a fraction of this amount in order to marshal these resources on behalf of ALD research. With direct Foundation expenditures of less than $200,000 we have received capital and other investments of greater than $2 million (a 10x boost to our seed investment).
Given the promising results seen, a biotech company based in Cambridge, Mass will be progressing the next study which will take place in the US, France, and the UK.
Mesynchymal Stem Cell (MSC) Therapy
Mesenchymal stem cells are multipotent stem cells -- often cultured from bone marrow cells -- that can differentiate into a variety of cells. This experimental therapy involves the use of MSCs taken from the bone marrow of adult donors and delivered into the brains of ALD patients who are at an advanced ALD stage. In the first phase trial of MSCs, the hope is that the MSCs applied to the brain would reduce the 6 to 18 month continued deterioration that is currently observed when transplansts are performed. If results are promising, then the patient may proceed with a conventional stem cell transplant.
The Mesynchymal Stem Cell (MSC) Therapy project involves scientists and physicians from University of Minnesota.
Previous Efforts Supported
A Gene Very Similar to The ALD Gene
The Stop ALD Foundation is also pursuing ALD homologue up-regulation. This is a way to encourage a gene that already exists in its normal form in all ALD patients to "over-express" so that it could compensate for the initial ALD defect. Work in mice has led us to believe this could have actual impact on disease progression in ALD patients.
The Stop ALD Foundation arranged for GlaxoSmithKline (GSK), the world's second largest pharmaceutical company, to share a small part of their library of compounds with the Austrian lab that is the leader in this category of ALD research. A series of experiments have been designed and promising results have begun to emerge.
Again, as a result of The Foundation "seeding" this work by investing a relatively small amount of resources, we are hopeful this project will now be pursued more aggressively. We will monitor progress in Europe, and we intend to participate as further needs may arise.
Transcriptomics: Predicting an ALD Child's Fate and Finding New Pharmaceutical Compounds to Help
Transcriptomics, is aimed toward learning more about the various forms of ALD. This may offer two broad categories of opportunities. First, once pathways and mechanisms are better described and understood, specific targets can then be identified where pharmaceutical intervention may prevent or ameliorate clinical signs.
Another area of interest is prediction of disease phenotype (how the disease "presents itself" in a particular child). Given today's therapies, there would be tremendous value in predicting whether a particular young boy was facing cerebral involvement in the near future, or whether he was destined to suffer from AMN as an adult.
Current stem cell therapies (both bone marrow and cord blood transplantation) are very risky procedures and often, the outcome is better if performed when the patient is younger. If the family and their doctors could have a definitive technique to predict whether a young child was going to have a deadly cerebral onset as a child, that technique would be an extremely useful tool when making the decision if and/or when to transplant a particular patient.
We must remind ourselves that we still do not fully understand the pathology of this dreadful disease. Many questions still exist: What role (if any) is played by the elevated long chain fatty acids? Why do males who carry identical gene mutations have different forms of ALD? Why do some female carriers show AMN symptoms (e.g., walking and bladder control problems) and others don't? Can the form of disease presentation be predicted? The answer to all these questions, and many more, is, unfortunately, at the present time, "we don't know."
In an effort to better understand the mechanism of the disease, The Foundation arranged for an interactive and cooperative Transcriptomics project between GlaxoSmithKline (GSK) and Dr. Patrick Aubourg (INSERM, Paris, France). Transcriptomics is the description and study of gene expression patterns.
Most fortunately, we have been able to utilize hundreds of thousands of dollars worth of equipment and expertise in order to better describe and understand the complex protein production and interactions that occur in the various human ALD pathological states.
A paper was published and some of this data is being analyzed so that useful interpretations can be made. The next steps with this technology will be to try to develop a better prediction technique for patients.