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Research Plan for Ataxia-Telangiectasia

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Department of Health and Human Services
National Institutes of Health
National Institute of Neurological Disorders and Stroke

February 2006

Table of Contents

Executive Summary
Background
   Description of ataxia-telangiectasia
   Strategic planning process
The Plan for A-T Research
   Understand the molecular basis of the symptoms of A-T
   Develop promising therapeutic approaches for A-T
   Develop resources to accelerate A-T research
   Stimulate progress through interdisciplinary interactions

Executive Summary

The NIH has developed a research plan for ataxia-telangiectasia (A-T) in response to interest from the scientific, medical, and patient communities, as well as from Congress. The plan is a product of the Trans-NIH A-T Research Working Group, which includes program directors from the National Institute of Neurological Disorders and Stroke (NINDS), National Heart, Lung, and Blood Institute (NHBLI), National Institute of Environmental Health Sciences (NIEHS), National Cancer Institute (NCI), National Eye Institute (NEI), National Institute of General Medical Sciences (NIGMS), National Human Genome Research Institute (NHGRI), National Institute on Aging (NIA), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), and Office of Rare Diseases (ORD). Representatives from three A-T patient groups (A-T Children's Project, A-T Ease, and A-T Medical Research Foundation) offered recommendations for research goals, as did participants in the 2005 International Workshop on Ataxia-Telangiectasia, ATM and the DNA Damage Response.

This plan for A-T research is intended to be comprehensive in that it addresses basic through clinical research, spans the short and long term, and serves the entire research community, including scientists supported by the NIH, patient groups, and industry. At the same time, the plan aims to be realistic in focusing on achievable high priority goals and allowing for flexibility as the science evolves. The broad objectives are to:

  • Understand the molecular basis of the symptoms of A-T;
  • Develop promising therapeutic approaches for A-T;
  • Develop resources to accelerate A-T research; and
  • Stimulate progress through interdisciplinary interactions

The NIH is committed to promoting progress in A-T research through all promising channels and will reevaluate NIH efforts on a regular basis as the science evolves and opportunities arise.

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Background

Description of ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is a rare, progressive childhood disease that affects multiple organ systems. A-T is characterized by considerable variability in the combinations and severity of symptoms. The first signs of the disease are neurological: delayed development or deterioration of motor skills, poor balance (ataxia), involuntary movements, drooling, abnormal eye movements, and slurred speech. The loss of Purkinje neurons in the cerebellum of the brain is the hallmark pathology of A-T, but peripheral neuropathy develops in many patients later in life. Children with A-T are generally not cognitively impaired, although some patients can suffer from short-term memory loss. A-T is also characterized by telangiectasias (dilated "spider" veins), which usually appear in the eyes and sometimes on the surface of the ears and cheeks. Individuals with A-T are particularly sensitive to ionizing radiation, such as X-rays. About 20% of individuals with A-T develop acute lymphocytic leukemia or lymphoma. Most individuals with A-T have a weakened immune system, and many are susceptible to recurrent respiratory conditions, which are the most common cause of death. However, these respiratory conditions are not always the result of infections. Occasional features of the disease include insulin-resistant diabetes mellitus, premature graying of the hair, and delayed physical and sexual development. Notably, A-T is frequently misdiagnosed, with the most common misdiagnosis being cerebral palsy.

There is presently no cure for A-T, nor is there a way to slow the progression of the disease. Current treatment is symptomatic and palliative. Physical and occupational therapy may help maintain flexibility and muscle strength. Speech therapy may also be needed. Gamma-globulin injections help to supplement a weakened immune system. High-dose vitamin regimens may also be used. The prognosis for individuals with A-T is poor, with death occurring in the teens or early 20s.

A 1986 study estimated that the incidence of A-T in the United States ranged from 3 to 11.3 in 1 million births (Swift et al., Am J Hum Genet., 1986), but a later study of mutation frequency would suggest that this is an underestimate (Uhrhammer et al., Atlas Genet Cytogenet Oncol Haematol., 2002). The A-T Children's Project estimates the incidence of A-T to be approximately 1 in 40,000 births but notes that the disease may be much more common, since some children with A-T are misdiagnosed or die before they are accurately diagnosed.

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Strategic planning process

In response to interest from the scientific, medical, and patient communities, as well as from Congress, the NIH has developed a research plan for A-T and a general mechanism for coordinating A-T research efforts. As A-T is a multi-system disease, the NIH has formed an inter-Institute group to coordinate and focus NIH efforts related to A-T. This Trans-NIH A-T Research Working Group is comprised of program staff from Institutes that have an interest in A-T, including the National Institute of Neurological Disorders and Stroke (NINDS), National Heart, Lung, and Blood Institute (NHBLI), National Institute of Environmental Health Sciences (NIEHS), National Cancer Institute (NCI), National Eye Institute (NEI), National Institute of General Medical Sciences (NIGMS), National Human Genome Research Institute (NHGRI), National Institute on Aging (NIA), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), and Office of Rare Diseases (ORD). Discussion at the first two working group meetings covered ongoing research activities, key challenges to the field, and strategies to promote progress. To ensure adequate attention to the interests of A-T patients, the second meeting of the working group also included representatives from three A-T patient groups (A-T Children's Project, A-T Ease, and A-T Medical Research Foundation). The working group's discussions, together with recommendations from the 2005 International Workshop on Ataxia-Telangiectasia, ATM and the DNA Damage Response (sponsored in part by NINDS), formed the basis for the A-T research plan.

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The Plan for A-T Research

The following plan for A-T research is intended to be comprehensive in that it addresses basic through clinical research, spans the short and long term, and serves the entire research community, including scientists supported by the NIH, patient groups, and industry. At the same time, the plan aims to be realistic in focusing on achievable high priority goals and allowing for flexibility as the science evolves. Three of the four sections describe the state of the field and outline research goals to address the most imminent challenges. The first two sections address the key scientific questions. The third section considers research resources, and the fourth offers a philosophy on how to move the field forward.

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Understand the molecular basis of the symptoms of A-T

Developing treatments for A-T will require a better understanding of its molecular and pathological basis. A major breakthrough in understanding A-T came in 1995 with the identification of the disease gene, ATM (Ataxia-Telangiectasia, Mutated). This gene encodes the ATM protein, which plays a key role in repairing double-strand breaks in DNA. ATM-mediated DNA repair is important in several different contexts. X-rays, chemicals that mimic the effects of X-rays, and free radicals (extremely reactive molecules that form during normal metabolic processes) can trigger random double-strand DNA breaks. Failure to properly repair these breaks can lead to mutations, cell death, or cancer. In addition, cells of the immune system normally induce double-strand DNA breakage and reunion within antibody-encoding genes during the process of immune system maturation. These DNA rearrangements create the enormous diversity in antibody structures that enable the immune system to respond to a variety of threats. In A-T patients, the disruption of this ATM-dependent process leads to the immune system dysfunction characteristic of A-T.

While researchers have made much progress in understanding the molecular details of ATM-mediated DNA repair, many questions remain about how the loss of ATM causes A-T symptoms to develop. Why are A-T patients more susceptible to leukemia and lymphoma than to other types of cancers? How do ATM mutations cause selective degeneration of Purkinje neurons in the cerebellum, leading to a variety of neurological symptoms? Loss of cerebellar cells is not sufficient to explain all of the neurological symptoms associated with A-T, and these non-cerebellar effects warrant further investigation. Why do some A-T patients develop pneumonia or chronic lung disease? What accounts for the variability in the presentation and severity of A-T? Some A-T patients appear to have little-to-no functional ATM protein, yet only exhibit mild symptoms of A-T. Do genes other than ATM contribute to or modulate A-T? What are these other genes? Is there a correlation between the nature and location of mutations and disease severity? Do external factors contribute to the severity of A-T symptoms? There are anecdotal reports of A-T patients whose symptoms worsened during or following an infection, and mutations in ATM correlated with arsenic sensitivity in several studies of cultured cells.

The NIH supported the discovery of the ATM gene and continues to fund basic research to understand the normal functions of the ATM protein and how its loss causes disease. The NIGMS currently funds several studies on the mechanism of action of ATM in normal cells. The NCI supports studies on the role of the ATM protein in the development of a variety of cancers. The NIA supports research on the role of the ATM gene in regulating cell aging, both in mice and in cell culture models. The NINDS funds research on the role of ATM specifically in the nervous system. For example, NINDS is currently sponsoring a study to analyze and correlate the anatomical, molecular, and physiological abnormalities in the brain of a mouse model of A-T. The NIH has also supported conferences on the biology of A-T, including the 2005 International Workshop on Ataxia-Telangiectasia, ATM, and the DNA Damage Response; a 2001 workshop on the role of DNA damage-response defects in neurogenetic disease; a 1999 workshop on the neurobiology of A-T; and a 1998 workshop on the neurodegeneration that occurs in A-T.

The biotechnology company Perlegen Sciences is considering an effort to identify genes that contribute to or modify the A-T phenotype. Perlegen Sciences will use high-throughput sample preparation methods and ultra-high density oligonucleotide arrays to sequence millions of small, variable regions of DNA across the human genome rapidly, in search of DNA regions that are shared among A-T patients and thus may contribute to A-T onset and progression.

Specific research goals in this section include:

  • Determine the full mechanism of ATM activation, including how ATM is recruited to sites of DNA damage
  • Determine whether and how particular ATM mutations correlate with disease severity
  • Characterize neuronal manifestations of A-T outside the cerebellum
  • Investigate the ATM-mediated damage response in the nervous system with a special emphasis on the cerebellum; understand how differentiated cells in the nervous system differ from dividing cells in other tissues in terms of the ATM-mediated DNA damage response
  • Determine the relationship between A-T and susceptibility to leukemia and lymphoma
  • Determine the mechanisms that lead to cancer in A-T patients
  • Determine the cause(s) of lung disease in A-T individuals, especially pulmonary failure
  • Determine whether external factors (such as infection or toxins) influence the severity of A-T symptoms
  • Identify genetic modifiers of ATM that affect the severity of A-T

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Develop promising therapeutic approaches for A-T

Researchers are exploring therapeutic strategies that target the underlying causes of A-T, rather than just the symptoms. Some of these strategies are already in clinical trials. Others are in much earlier stages of development.

Two general approaches target the earliest event that fails in A-T-the production of functional ATM protein. The first involves drug screening. NINDS-funded researchers recently identified three aminoglycoside antibiotics that can trick cultured cells into ignoring truncation-inducing mutations in the ATM gene so that the cells can express functional, full-length ATM protein from the mutated gene. This promising discovery raises the possibility of high-throughput screening for other drugs with this property. The second approach is to replace the defective ATM gene with the normal gene, i.e., gene therapy. However, gene therapy faces many challenges, regardless of the disease it aims to cure, from ensuring that the therapeutic gene inserts safely into the genome to regulating when, where, and how much it is expressed.

Other strategies seek to compensate for the lack of functional ATM protein by recalibrating the activities of other DNA repair proteins and/or reducing oxidative stress. Studies of ATM-deficient mice and A-T patients indicate that oxidative stress could contribute to some of the clinical features of A-T. Cells experience oxidative stress during normal metabolic processes. Cells in oxidative stress produce harmful levels of free radicals, molecules with unpaired electrons that are extremely reactive. Free radicals damage components of the cells' membranes, proteins, or genetic material by "oxidizing" them-the same chemical reaction that causes iron to rust. Several laboratories are developing and testing strategies to counteract this process. The NIEHS is currently supporting a study to investigate a possible therapeutic role for antioxidants in a mouse model of A-T. The A.I. duPont Hospital for Children in Delaware is conducting a pilot clinical trial to test a cocktail of antioxidants and vitamin cofactors in children with A-T. The A-T Clinical Center at John Hopkins Hospital, funded by the A-T Children's Project, is conducting a Phase I trial with a combination of nicotinamide (an inhibitor of the enzyme PARP-1, which plays a role in DNA repair) and alpha lipoic acid (an antioxidant).

Eventually, it may be possible not only to prevent cell loss, but also to replace damaged cells. This science is still in the very early stages; scientists currently are exploring ways to coax stem cells to differentiate into various types of neuronal cells, such as the cerebellar Purkinje cells that degenerate in A-T.

Specific research goals in this section include:

  • Conduct high-throughput drug screens for A-T
  • Conduct pre-clinical studies on promising drug leads
  • Conduct multi-site clinical trials (including international partners) on the most promising drug candidates
  • Investigate the therapeutic potential of activators/repressors of proteins involved in ATM-mediated DNA repair and other pathways associated with A-T
  • Explore possibilities for gene and stem cell therapies

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Develop resources to accelerate A-T research

Several types of research tools are critical for exploring the biology of A-T and developing therapeutics. Increased access to post-mortem tissue samples from A-T patients would help enable research into the pathology of A-T. The NICHD and A-T Children's Project support a brain and tissue bank for A-T at the University of Maryland, and researchers should be encouraged to make the most of this resource. Researchers need to develop better molecular tools to study the mechanisms underlying A-T, in particular, antibodies that recognize the proteins that function in DNA repair. There is a critical need for antibodies to human ATM that are specific enough for use in immunohistochemistry. Researchers also need to identify biological markers of A-T, not only to diagnose A-T and study its progression, but also to measure the effects of potential therapeutics. High-throughput drug screening requires the development of appropriate assays (tests). The NINDS has encouraged the A-T research community to develop a strategy to screen for A-T therapeutics and supported a 2004 workshop on A-T assay development. Extramural investigators can submit validated A-T assays to the NINDS-supported high-throughput drug screening facility at the Southern Research Institute in Birmingham, Alabama for screening against a collection of 100,000 compounds, or take advantage of the NIH Roadmap drug screening programs. Researchers also must develop small animal models that exhibit the neuronal symptoms of A-T for preclinical testing of promising therapeutics that emerge from drug screening and other lines of research. While there are mouse strains available in which the ATM gene is deleted or "knocked out," and they do exhibit some A-T characteristics, these strains do not exhibit the neuropathology characteristic of A-T patients.

Specific research goals in this section include:

  • Develop better animal models of A-T
  • Develop assays for high-throughput drug screening
  • Encourage the banking and use of post-mortem tissue from A-T patients
  • Generate mono-specific antibodies against ATM and other proteins involved in the DNA damage response, especially those useful for immunohistochemistry
  • Develop biomarkers for basic, preclinical, and clinical studies of A-T

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Stimulate progress through interdisciplinary interactions

Accelerating research on rare diseases like A-T is challenging, in part, because the research communities dedicated to these diseases are relatively small. Identifying and seizing promising opportunities may require vision beyond conventional boundaries. The broad representation of Institutes on the Trans-NIH A-T Working Group encourages this kind of vision. Researchers working on other types of neurodegenerative diseases and cancers may make discoveries that will suggest therapeutic approaches for A-T. Even diseases that seem very different from A-T may have some similarities at the molecular level that may be insightful. For example, researchers working on cystic fibrosis and muscular dystrophy conduct the same kinds of "read-through" drug screens that researchers are considering for A-T. It will be interesting to see if the same compounds emerge from these screens and can be used to treat subsets of genetic disorders that share similar mechanism of initiation. The NIH is experimenting with a variety of approaches for drug development. Some of these approaches may serve as models for A-T, and vice-versa; already we have witnessed how research on A-T-associated mutations has offered insight into cancers of the breast, ovary, and lymphoid system. Also, A-T has become the prototype for an ever-expanding group of radiosensitive disorders, most of which also share cancer susceptibility and immunodeficiency. It may be productive to hold workshops on A-T and related disorders that include scientists with expertise in these other areas, even if they are initially unfamiliar with A-T. The Trans-NIH A-T Working Group is committed to promoting progress in A-T research through all promising channels and will reevaluate NIH efforts as the science evolves and opportunities arise.

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Last updated February 10, 2006