20 years of research into leukodystrophies

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Virgil Curtis
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1 Chronology 20 years of research into leukodystrophies st treatment of adrenoleukodystrophy with Lorenzo's oil in a human 1993 Identification of the gene responsible for adrenoleukodystrophy 1994 Isolation of the gene responsible for Krabbe disease st attempt at in vitro gene transfer for metachromatic leukodystrophy st animal model for metachromatic leukodystrophy st animal model for adrenoleukodystrophy st attempt at in vitro gene transfer for Krabbe disease 1999 Culture of myelin cells in vitro 2000 Results of the 1 st gene therapy clinical test for Canavan disease 2001 Identification of the 1 st gene responsible for MLC illness st treatment of Canavan disease by lithium in the animal 2003 Progression of adrenoleukodystrophy: help in prediction by MRI 2004 Proof of concept for gene therapy against metachromatic leukodystrophy in the animal 2005 Proof of concept for gene therapy against adrenoleukodystrophy in the animal st clinical test of gene therapy against adrenoleukodystrophy st clinical test of substitutive enzymotherapy for metachromatic leukodystrophy 2008 Development of an animal model for adult Refsum disease st clinical test of cell therapy against Pelizaeus-Merzbacher disease First results of the clinical test of gene therapy against adrenoleukodystrophy st clinical test of gene therapy against metachromatic leukodystrophy 2011 Reprogramming of cells from patients with adrenoleukodystrophy into ips cells Identification of the gene responsible for TACH leukoencephalopathy 2012 Results of the cell therapy trial against Pelizaeus-Merzbacher disease Key figures Funding of medical research by ELA since 1992: 34.5 Million Number of research programs funded since 1992: 434 1

In 1992, less than ten leukodystrophies were known to the medical community, such as adrenoleukodystrophy, metachromatic leukodystrophy or Pelizaeus-Merzbacher disease.

However, a third of leukodystrophies still remain undiagnosed. A special effort is implemented by ELA to identify the genes responsible for these leukodystrophies known as "undetermined".

2 In 1992, less than ten leukodystrophies were known to the medical community, such as adrenoleukodystrophy, metachromatic leukodystrophy or Pelizaeus-Merzbacher disease. With the progress of genetics, the genes responsible for these illnesses have been identified (ABCD1, ARSA and PLP1, respectively). Over the last 20 years, new leukodystrophies have been discovered. Currently, over twenty are enumerated. In parallel, the genetic cause of many of these new illnesses has been identified, offering the families the possibility of a molecular diagnosis and genetic counselling. However, a third of leukodystrophies still remain undiagnosed. A special effort is implemented by ELA to identify the genes responsible for these leukodystrophies known as "undetermined". Examples of new leukodystrophies identified since 1992 New leukodystrophies CACH Syndrome Megalencephalic leukoencephalopathy with subcortical cysts (or MLC) TACH leukoencephalopathy Adult-onset autosomal dominant leukodystrophy (or ADLD) Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) Genes EIF2B MLC1, HEPACAM POL3RA, POLR3B LMNB1 EARS2 To better understand the mechanisms which lead to the illness, it is essential to collect biological samples from patients and to develop animal models for leukodystrophies which contribute in parallel to the evaluation of therapeutic strategies. Among the animal models created over the last 20 years, we may cite the mouse models for metachromatic leukodystrophy (1996), adrenoleukodystrophy (1997), adult Refsum disease (2008) or CACH syndrome (2010). For example the mouse model for adrenoleukodystrophy enabled researchers to explain the oxidative stress linked to the illness and identify therapeutic targets for keeping it under control. Since 1992, different types of therapeutic approaches have been developed and tested for leukodystrophies: 1. Nutritional therapy Starting in 1992, Lorenzo's oil, an oil enriched in oleic acid and erucic acids, associated with a diet involving reduced very long-chain fatty acids has been tested on children suffering from adrenoleukodystrophy. This treatment was developed by Augusto and Michaela Odone, the parents of Lorenzo who suffered from the illness, and enables doctors to normalize plasmatic levels of very long-chain fatty acids which are characteristic of the illness. However this treatment has no effect on cerebral forms of the pathology. With adult Refsum disease, there is an abnormal build-up of phytanic acid so a good level of control of plasmatic levels of this compound improves the patient's health and prevents the development of certain of the disease's more serious complications. In the 1960s, a well-adapted nutritional diet was prescribed for patients and this helped maintain very low levels of phytanic acid. This diet is continually being enriched and improved.

2. Pharmacological therapy Over the last 20 years, many medicines have been the subject of clinical tests for different leukodystrophies. Unfortunately none have yet proved effective.

3 2. Pharmacological therapy Over the last 20 years, many medicines have been the subject of clinical tests for different leukodystrophies. Unfortunately none have yet proved effective. However there are new candidate drugs to be tested on animal models or on humans: - Adrenomyeloneuropathy: cocktail of 3 antioxidants (vitamin E, lipoic acid and N-acetylcysteine), 4-aminopyridine, pioglitazone, therapy to reduce very long-chain fatty acids - Metachromatic Leukodystrophy: therapy to reduce substrates - Alexander disease: rapamycin, lithium, αb-crystalline, Nrf2 - Canavan: lithium - Pelizaeus Merzbacher disease: minocyclin - Biotin responsive leukodystrophy: biotin 3. Enzyme-replacement therapy Metachromatic Leukodystrophy In 2007, the Zymenex Laboratory in Denmark tested enzyme replacement therapy using the human arylsulfatase A enzyme (called Metazym) to treat metachromatic leukodystrophy. During this test run by the Shire HGT Laboratory, the enzyme was given to patients intravenously every 2 weeks. This treatment was found to be ineffective so the development of this formulation of an enzyme derived from non-human cells was stopped. A new formulation of the enzyme derived this time from human cells was next developed by Shire and called the HGT-1110 enzyme. This is currently being tested on patients suffering from metachromatic leukodystrophy in clinical tests in which the enzyme is directly injected into the central nervous system of the patients once a fortnight. Krabbe disease IN 2011, the Danish Laboratory Zymenex obtained Orphan Drug Designation Approval in Europe and the United States for its enzyme Galaczym. The orphan designation enables pharmaceutical laboratories to develop treatments for rare illnesses thanks to incitation measures aimed at promoting research, development and the designated medicine being put onto the market. Clinical testing of the effects of Galaczym should be starting soon.

4. Gene therapy The first experiments involving in vitro gene transfers for leukodystrophies were run in the 1990s using retroviral vectormedicines.

4 4. Gene therapy The first experiments involving in vitro gene transfers for leukodystrophies were run in the 1990s using retroviral vectormedicines. Given the risks associated with the development of leukaemia, no clinical tests were run on these vectors for leukodystrophies. Progress made in the field of virology has led to the development of new, safer vector-medicines which were tested on animal models for leukodystrophy from the 2000s onwards. Once the concept had proved effective with animals, clinical tests were run for Canavan disease, adrenoleukodystrophy (2006) and metachromatic leukodystrophy (2010): Canavan disease In 2000, the results of the first gene therapy tests for leukodystrophies were published. These tests took place in New Zealand and involved two patients suffering from Canavan disease. A non-viral vector transporting the normal GALC gene - which the patients lack - was injected directly into the ventricular system of the brain. Early results seemed encouraging but a larger-scale study was required. In 2002, this new study took place at the Robert Wood Johnson Medical Center in New Jersey (USA). This time a vector-medicine of the AAV2 viral type was used to administer the normal GALC gene to patients by intracerebral injection in 6 different places in the brain. No scientific results have been published as yet by the researchers but according to the American Canavan Foundation, the parents of the patients treated in this way have reported clinical improvement in their children. Currently promising new results with gene therapy animal testing at the University of Massachusetts (USA) are the subject of interest. A new type of AAV vector-medicine carrying the normal GALC gene injected intravenously into mice has been found to slow the development of the illness and restore normal levels of the GALC enzyme. Adrenoleukodystrophy Until 2006, cerebral adrenoleukodystrophy in children was treated using bone marrow transplants from donors. This approach was of course limited by the rarity of donors and by the risk of serious complications. In this new approach, the doctors opted to use autotransplantations combined with gene therapy. Stem cells of bone marrow were taken from patients then corrected in the laboratory before being reinjected. Certain of these cells will go directly towards the patient's brain by a natural mechanism and play a corrective role. During the tests, a vector-medicine derived from the modified and deactivated AIDS virus was used to introduce the normal ABCD1 gene into the patient's bone marrow cells. This discovery opens up new prospects for treating other sorts of leukodystrophy and should also be of benefit for other more frequent diseases (sickle-cell disease, Beta-Thalassemia, immunodeficiencies, Parkinson's disease etc.).

Four children were chosen who suffered from the cerebral form of adrenoleukodystrophy at a pre-symptomatic stage with progressive cerebral demyelination.

The results for the first two children treated were published in the prestigious scientific journal "Science".

5 Four children were chosen who suffered from the cerebral form of adrenoleukodystrophy at a pre-symptomatic stage with progressive cerebral demyelination. There were no compatible bone marrow donors but they were able to benefit from this innovative treatment. The results for the first two children treated were published in the prestigious scientific journal "Science". After months of monitoring, 10 to 15% of the two patients' blood cells were still expressing the ALD protein which had previously been undetectable. Four to five times more of the normal ABCD1 gene was expressed by these cells in comparison with the muted gene. From a neurological standpoint, the two children's demyelinating cerebral lesions evolved up until the 14 th - 16 th month after the transplant but remained stable from then on. The researchers intend to move forward from these encouraging results to carry out tests on more patients in Europe and the USA. ELA Funding: 1.5 Million Metachromatic Leukodystrophy An equivalent test to those run for gene therapy in adrenoleukodystrophy is currently being carried out in Milan for metachromatic leukodystrophy. Eight children with metachromatic leukodystrophy will be transplanted with their own bone marrow cells genetically corrected using a vector-medicine derived from the AIDS virus and which transports the normal human ARSA gene. The aim of this study is to evaluate the levels of innocuousness and effectiveness of this treatment. Up to now, three patients with a late-onset pre-symptomatic infantile form of the illness have been treated. No serious side effects from the treatment have been observed yet. Given the way the illness has developed in the two untreated brothers of the first patient, this patient should already have developed the first symptoms of the illness at 18 months and been in a wheelchair by 30 months. Instead at age 28 months, the patient is able to stand up alone and can walk and run with help. Although these first results are encouraging, we need to wait to the end of the test to draw conclusions. ELA Funding: 298, 000 A second set of gene therapy tests for metachromatic leukodystrophy is being prepared in France. Like the previous test, it will study levels of innocuousness and effectiveness of an AAV10 vector-medicine with the normal human ARSA gene. This will be given to the patient by intracerebral injection in 12 different places on the brain. If the project receives the required regulatory authorizations quickly, the tests should start in 2013 and treat 5 patients with a rapidly progressing form of metachromatic leukodystrophy. ELA Funding: 2.5 Million

5. Cell therapy Pelizaeus Merzbacher disease The first therapeutic tests of the effects of stem cell transplants for patients suffering from Pelizaeus Merzbacher disease have just finished at the

6 5. Cell therapy Pelizaeus Merzbacher disease The first therapeutic tests of the effects of stem cell transplants for patients suffering from Pelizaeus Merzbacher disease have just finished at the University of California, San Francisco (USA). This is the first test designed to treat a neurodegenerative illness resulting from myelin deficiency. The research objective was to test the levels of innocuousness and effectiveness of a treatment with four children suffering from the severe form of the illness over a period of a year. The children received neurosurgical transplants of human neural stem cells called HuCNS-SC and then for the following 9 months were given immunosuppressive drugs to prevent the rejection of the transplanted stem cells. No adverse effects were observed in the year following the transplants. Neurological functions very slightly improved in 3 of the 4 patients treated. MRI brain analysis revealed that the stem cells had been durably implanted along with evidence of the formation of myelin in the transplant zone. Larger-scale clinical tests are likely to be developed in the near future and will include a European medical centre Adult cerebral adrenoleukodystrophy Bone marrow stem cell transplants carried out at the very start of the illness are the only way of stabilizing or reversing cerebral lesions to the myelin of children with the cerebral form adrenoleukodystrophy. At a later stage in the development of the illness this treatment is ineffective and can even be harmful and the procedure has a high mortality rate. Currently only around fifteen adults have benefited from this therapeutic approach. An international group of expert neurologists and haematologists is currently working on defining a set of recommendations for the medical community to harmonize the treatment procedure for adult patients and setting up a register of transplanted patients to monitor their progress. In 20 years, a great deal of scientific and medical progress has been made in diagnosing leukodystrophies and in understanding and treating these illnesses. New tools and models are now available for researchers and doctors to test new innovative technologies and therapies.

Adrenoleukodystrophy gene therapy: News of the four treated children Currently four children suffering from ALD have received this experimental treatment - first Andy and Angel followed by Andres and

7 Adrenoleukodystrophy gene therapy: News of the four treated children Currently four children suffering from ALD have received this experimental treatment - first Andy and Angel followed by Andres and Clement. We interviewed these four ELA Spain and ELA France families to get up to date on the children's news. As a reminder, the results of the ALD gene therapy carried out by Professor Patrick Aubourg and Dr Nathalie Cartier were published in November 2009 in the specialist journal "Science". ELA has been monitoring research into ALD since its creation in 1992 and is the largest source of research funding with nearly 8 million euros invested over a 20 year period. In this approach, the doctors chose to combine autotransplantations with gene therapy for children who could not receive more conventional bone marrow transplants because of a lack of donors. Stem cells of bone marrow were taken from patients then corrected in the laboratory before being reinjected. Andy is 14 and comes from Spain. He was the first patient to receive this experimental therapy in August His big brother Oscar was diagnosed first as having the illness which enabled doctors to rapidly diagnose Andy. Today Andy is doing well, his condition has not evolved since his last appointment with Professor Aubourg in Paris and he is still taking corticosteroids for his adrenal insufficiency. No complications have been observed and he is stable. Andy's life is close to normal and he goes to a special school because of his learning difficulties.

Angel is a 12-year-old Spanish boy who was also diagnosed following the diagnosis of his elder brother.

The neurological damage observed after stabilization of the treatment has not worsened. His vision was affected along with his short-term memory and sense of direction.

Like Andy, Angel takes daily corticosteroids and has a check-up in Paris with Professor Aubourg every 6 months. Andrès is also from Spain and is 12 years old.

8 Angel is a 12-year-old Spanish boy who was also diagnosed following the diagnosis of his elder brother. Angel is the second patient to have benefited from this experimental therapy which he received in January Today Angel is doing well. The neurological damage observed after stabilization of the treatment has not worsened. His vision was affected along with his short-term memory and sense of direction. Nonetheless he has a normal life just like other boys of his age. He still goes to school even if he cannot keep up the same pace as his classmates. Like Andy, Angel takes daily corticosteroids and has a check-up in Paris with Professor Aubourg every 6 months. Andrès is also from Spain and is 12 years old. He was diagnosed when hospitalized for a serious gastroenteritis which in fact stemmed from adrenal insufficiency, a defect which is commonly linked to ALD. Andres received the gene therapy in June Four years later, he still has difficulties but his mum has noticed certain improvements. He is more active and moves more than before. Andres has no short-term memory and has been going to a special school since He is making progress and today lives a normal life while also taking daily corticosteroids. Clément is 6 years old and was the last patient to be treated with gene therapy in September Two years on from that, the little boy is doing well. He lives a perfectly normal life, he runs, goes to the swimming pool, rides his bike and started primary school at the end of the summer holidays. Clement is also taking daily corticosteroids without any problems to treat his adrenal insufficiency.

Myelination, Leukodystrophies and Hypomyelinating Disorders. Florian Eichler, M.D. Massachusetts General Hospital Harvard Medical School

Myelination, Leukodystrophies and Hypomyelinating Disorders Florian Eichler, M.D. Massachusetts General Hospital Harvard Medical School Myelin Lipid bilayer enhanced by intrinsic and extrinsic proteins