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 and developing therapeutic approaches

  • Molecular biology of Alpha-1 Antitrypsin (AAT) expression
    • Mechanisms of AAT synthesis, folding and secretion
    • Molecular pathology of Z AAT gene expression
  • Animal Model Development
    • Development of an AAT deficient animal model for lung
    • Development of an AAT deficient animal model for liver
  • Lung-Focused Research
    • Determinants of lung growth, turnover, maintenance and regeneration
    • Mechanisms of tissue destruction, response to injury, and inflammation
  • Liver-Focused Research
    • Determinants of liver growth, maintenance, turnover and regeneration
    • Mechanisms of hepatocellular toxicity and liver damage
  • Technology Development
    • Hepatocyte transplantation
    • Gene therapy: enhancement, replacement, extinction and repair
    • Epigenomics of Alpha-1 gene regulation
    • Small molecule anti-proteases
    • Small molecule, high through-put library screening
  • Stem Cell Research and Regenerative Medicine
    • In vitro disease modeling, drug screening, and personalized medicine
    • Stem cell-based therapies
    • Lung and liver tissue development and engineering artificial organs

Clinical Research: Identifying Alphas and defining the epidemiology
and natural history of AAT Deficiency

  • Epidemiology and Natural History of AAT deficiency
    • Impact of primary care and allied health care providers in detecting alpha-1
    • Prenatal and newborn screening pilot studies
    • Predicting course and outcomes
    • Defining the risk of clinical manifestations in heterozygote carriers
      • Longitudinal study of PI*MZ individuals
    • Natural history following lung transplantation
    • Natural history of lung disease following liver transplantation
  • New diagnostic technologies
  • Modifier genes or epigenomic influences affecting Lung and Liver in AAT deficient individuals
  • Transcriptomic and proteomic correlates of lung disease progression or stability
  • Role of inflammation in the pathogenesis of AAT lung disease
  • Establishment of effective clinical outcomes measures in AAT deficiency
    • Biomarkers of early lung or liver disease or of disease exacerbations
    • MRI, Quantitative CT scanning, fibroscan or other new modalities to assess lung or liver disease progression and response to therapy
  • Quality of life, patient reported outcomes, healthcare utilization, and symptom management
  • Environmental modifiers of lung and liver disease in AAT deficient individuals
    • Microbiome as a potential disease modifier
    • Gene-environment interactions
  • Clinical manifestations of AAT Deficiency other than in the lungs and liver

 Evaluating Novel Therapeutic Approaches

  • Alpha-1 antitrypsin augmentation therapy
    • Development of recombinant therapy approaches
    • Development of aerosolized AAT therapy
    • Determining the utility of AAT therapy in deficient lung transplant recipients
    • Therapeutic dose analysis
  • Improving outcomes in lung and liver transplant recipients
    • Use in post-transplant rejection
  • Treatment of pathophysiological manifestations (e.g., hyperinflation, cirrhosis, cholestasis) of AAT deficiency in lung and liver
  • Anti-inflammatory therapy
  • Small molecule antiprotease therapy
  • Cell-based therapies
  • Gene therapies
    • Gene replacement therapy
    • Enhancing or silencing AAT expression
  • Chemical chaperone therapy
  • Biomarkers as an index of therapy in lung and liver

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

  • Newborn testing/screening
  • Targeted detection
  • Social dimensions of living with A1ATD
  • Equitable access to, and distribution of, medical therapies
  • Impact of genomic information on Alpha-1 patients and their families
  • Impact of interventions on patient adherence and emotional well-being
  • Impact of Alpha-1 on families