Research Agenda

The Alpha-1 Foundation has spent considerable time and resources to devise a feasible and relevant research agenda

The Alpha-1 Foundation has spent considerable time and resources to devise a feasible and relevant research agenda. The process started at the strategic planning level, a formal exercise that the Foundation completed in 2000.

This global evaluation of the Foundation’s programs and research activities included input from both the existing AAT research network and from a wide range of associated organizations and experts. This strategic planning process included sessions involving focused planning groups, scientists, government representatives of the National Institutes of Health, Food & Drug Administration and written comments from the Center of Disease Control, and input from other Voluntary Health Agencies who are represented on the National Health Council. During the numerous strategic planning sessions, the major research foci were identified as well as gaps in scientific knowledge that needed to be addressed by further research.

The second stage in devising a research agenda involved the Alpha-1 Foundation’s Medical and Scientific Advisory Committee (MASAC), the Foundation’s primary medical advisory body, to evaluate the research areas identified by the strategic planning process on a regular (annual) basis. In 2001, an ad hoc committee was appointed by MASAC to carefully review the suggested research foci that were identified in the strategic planning process, and place these recommendations within the context of what is feasible to achieve scientifically with current expertise and technology. The ad hoc committee produced the research agenda shown below and it serves as a working document used by the grants award program for prioritizing the relevance of grant applications to the Foundation’s overall research goals. The use of the strategic plan and research agenda for evaluation of grant applications is only one use envisioned for the research agenda document. It has also been utilized to identify the most relevant topics for the critical issue workshops.

Agenda:

Basic Research: Identifying Targets & Developing Therapeutic Approaches

  1. Molecular biology of alpha-1 antitrypsin (AAT) expression
    • Mechanisms of AAT synthesis, folding and secretion
    • Molecular pathology of Z AAT gene expression
    • Development of an AAT deficient animal model
  2. Lung-Focused Research
    • Determinants of lung growth, turnover, maintenance and regeneration
    • Mechanisms of tissue destruction, response to injury, and inflammation
  3. Liver-Focused Research
    • Determinants of liver growth, maintenance, turnover and regeneration
    • Mechanisms of hepatocellular toxicity and liver damage
  4. Technology Development
    • Hepatocyte transplantation
    • Gene therapy: enhancement, replacement, extinction and repair
    • Stem cell isolation, repair and replacement
    • Small molecule anti-proteases
    • Small molecule, high through-put library screening

Clinical Research: Identifying Alphas & Defining the Natural History of AAT Deficiency

  1. Epidemiology of AAT deficiency
    • Targeted detection of AAT gene defects
    • Population screening for AAT gene defects
    • Approaches to promote routine annual pulmonary function testing in the primary care office or community setting
    • Defining the risk of clinical manifestations in heterozygote carriers
  2. Modifier genes affecting lung and liver in AAT deficient individuals
  3. Role of inflammation in the pathogenesis of AAT lung disease
  4. Establishment of effective clinical outcomes measures in AAT deficiency
    • Quantitative CT scanning to assess lung disease progression
    • Biomarkers of early lung or liver disease or of disease exacerbations
  5. Quality of life, healthcare utilization, and symptom management
  6. Environmental modifiers of lung and liver disease in AAT deficient individuals
  7. Clinical manifestations of AAT Deficiency other than in the lungs and liver

Translational Research: Evaluating Novel Therapeutic Approaches

  • Alpha-1 antitrypsin replacement therapy
  • Development of aerosolized AAT therapy
  • Determining the utility of AAT therapy in lung transplant recipients
  • Augmentation therapy post-lung transplant
  • Improving outcomes in lung and liver transplant recipients
  • Treatment of pulmonary hyperinflation
  • Anti-inflammatory therapy
  • Small molecule antiprotease therapy
  • Gene therapy
  • Gene replacement therapy
  • Enhancing AAT expression
  • Chemical chaperone therapy

Ethical, Legal & Social Issues Research: Eliminating Barriers for Alphas

  • Newborn testing/screening
  • Targeted detection
  • Social dimensions of A1ATD
  • Equitable distribution of medical therapies