I M P A C T
2025 RESEARCH & SCIENCE REPORT
Letter from the Scientific Director
Dear Friends,
This year marks the 30 anniversary of the Alpha-1 Foundation (A1F), a significant milestone and an opportunity to reflect on where we have come from, what we have accomplished, and the work that remains to be done. The purpose of this Impact Report is to carry out those tasks and to attempt to measure how effective we have been in accomplishing our goals. Since the last report five years ago, we have made significant progress as a community. We have navigated a pandemic, resumed in-person activities, and overseen a resurgence of research interest in Alpha-1 Antitrypsin Deficiency (AATD).
We can now cheer for multiple new therapeutic modalities being tested in clinical trials, an enviable and unique situation among genetic diseases and a welcome departure from prior years when there were few new treatment options on the horizon. We feel great urgency to make the most of this opportunity, and it is with that urgency in mind that we now take the measure of our prior accomplishments and look ahead.
This report documents the output of a robust and outstanding community of researchers, physicians, A1F staff, and patients working together towards a common goal. I hope you will share in the optimism that I feel when reviewing our progress and the position we now occupy as we look ahead. As always, we are guided and inspired by lessons learned from John and Fred Walsh, who taught us to be impatient in our expectations for progress and to remember to “Keep the Faith.”
Sincerely,
Andrew Wilson, MD A1F Scientific Director
25 years of Alpha-1 Foundationsponsored Research (1999 to 2024)
Promoting research with the vision of finding better treatments and ultimately a cure for AATD has been a major focus of A1F for the past 25 years. Investigatorinitiated grants have been the driving force of A1F’s research program from its inception in 1999, based on the time-tested principle in biomedical discovery that innovative ideas typically arise in the research community. Between 1999 and 2024, over $100 million has been invested in research. Of those funds, approximately 50% was directed at the peer-reviewed investigator-initiated grants program while the remainder was used to organize and publish the proceedings of scientific conferences, and to support the DNA & Tissue Bank and the Alpha-1 Research Registry along with other programs as resources for basic and clinical researchers.
A1F-sponsored research has had a significant impact on our understanding of the mechanisms leading to the clinical manifestations of AATD, and most of this information has been obtained through investigations supported by investigator-initiated grants (Figure 1).
Figure 1 Alpha-1 Foundation investigator-initiated grant program
The program is based on the concept that investigator-initiated research leads to scientific publications and is the basis of scientific meetings, which facilitate cross-pollination, amplifying the impact of new findings and informing the biotech and pharmaceutical companies in their quest for new therapeutic solutions. A1F support has the additional benefit of attracting and retaining the scientific workforce to focus on AATD. This document aims to summarize the scientific contributions of this research from 1999 to 2024.
A1F has issued 85 new grant awards to individual investigators totaling $14.1 million between 2019-2024 since the last impact report.
Applications for A1F funding are increasing. During the COVID-19 pandemic, applications for funding declined as research became more challenging to conduct and the time of physician-researchers was occupied with patient care. Applications for funding were at their lowest in 2020 and remained low for several years but have subsequently rebounded, as indicated in Figure 2. For the 2024-2025 cycle, we received the highest number of letters of intent (LOIs) to submit a grant proposal in the past 10 years.
Applicants come from a variety of institutions and countries: Cutting-edge research that advances the field can happen in many locations around the world. To leverage worldwide expertise in the service of AATD patients, A1F receives and funds research proposals from many different countries, representing many institutions.
Figure 2: FY19-FY26 Submission Breakdown
The home countries of A1F-funded investigators as well as the number of institutions they represent are listed in the charts below:
3: Location of A1F-Funded Investigators
4: Number of Institutions Receiving A1F Funding
Cultivating New Investigators: In addition to generating new knowledge that can benefit AATD patients, A1F support encourages researchers to study AATD, bringing new researchers into the field who in some cases go on to study AATD for long periods of time. Each year, A1F grants are awarded to PIs who have never previously applied for funding, demonstrating how the program functions to recruit new investigators.
Figure
Figure
Figure 5: New Investigators Receiving A1F Funding
Funding levels: The total amount of funds awarded by A1F to support research can vary from year to year based on several factors, including the number of meritorious applications received and availability of funds to commit for this purpose. Following the decline in applications and associated funds awarded from 2020-2022, A1F has increased total funds awarded in support of research grants in the past two fiscal years.
Figure 6: Total Funding from FY19-FY26
Table 1: A1F grantees and research topics from 2018-2024
YEAR GRANTEES
2019 Daniel Hebert, PhD
2019 Elizabeth Sapey, PhD
INSTITUTIONS
University of Massachusetts Amherst
University of Birmingham, UK
RESEARCH TOPICS
Alpha-1-antitrypsin folding and maturation in the cell
Causes of failure of opsonophagocytosis of nontypeable haemophilus influenzae in AATD
2019 Ross Edgar, MRes
2019 Andrew Wilson, MD
2019 Joseph Kaserman, MD
University of Birmingham, UK
Boston University
2019 David Lomas, M.D., PhD
2019 Rita Vanbever, PhD
2019 Bin Zhang, PhD
Boston University
University College London, UK
Universite Catholique De Louvain, Belgium
Cleveland Clinic Foundation
Clinical impact and mechanisms underlying rare variants of AATD
Contribution of Gain of Function Toxicity to AATD Lung Disease Pathogenesis
Defining PiMZ AATD Liver Disease Susceptibility with CRISPR Targeted Syngeneic iPSCs
Development of a diagnostic technology to image Z a1antitrypsin polymers in vivo
Development of a novel form of alpha1-antitrypsin for inhalation
ER-to-Golgi transport of alpha-1-antitrypsin
YEAR GRANTEES
INSTITUTIONS
2019 Andrew Wilson, MD Boston University
RESEARCH TOPICS
Functional characterization of risk modifier gene MAN1B1 in patient-derived hepatocytes
2019 Mariana Kirst, PhD University of Florida
2019 Karina Serban, MD National Jewish Health
2019 Stefanie Krajewski, PhD
2019 Pasquale Piccolo, PhD
2019 Emer Reeves, PhD
University of Tuebingen, Germany
Telethon Institute of Genetics and Medicine, Italy
Royal College of Surgeons in Ireland, Ireland
Gut Microbiota in Alpha-1 Antitrypsin Deficiency Liver Disease
Induced pluripotent stem cells-derived alveolar macrophages phenotype and function in AATD
MessengerRNA as a novel treatment option for alpha-1antitrypsin deficiency
Metabolic alterations in liver disease due to mutant Z alpha1-antitrypsin
Targeting neutrophil driven autoimmunity in patients with alpha-1 antitrypsin deficiency
2019 Susan Ferro-Novick, PhD
University of California, San Diego
2019 Richard Sifers, PhD Baylor College of Medicine
2019 Simon Lam, MD The Cleveland Clinic
The role of autophagy in the degradation of alpha-1 antitrypsin Z variant
Unconventional mechanics responsible for selecting the ATZ monomer for ERAD
Use of Electronic Medical Record and Pharmacy
Prescription Data to Improve Alpha-1 Antitrypsin Deficiency Testing
2020 Arlene Glasgow, PhD Royal College of Surgeons in Ireland
2020 Dawn DeMeo, MD, MPH Brigham and Women's Hospital
2020 Jeffrey Teckman, MD Saint Louis University
2020 Julia Heck, PhD, MPH
University of California, Los Angeles
A role for mitochondrial danger-associated molecular patterns (mtDAMPs) in AAT deficiency
Accelerated Aging and Alpha-1 Antitrypsin Deficiency
Alpha-1 Antitrypsin Deficiency Adult Clinical and Genetic Linkage Study
Birth outcomes among Alpha-1 Families
YEAR GRANTEES
INSTITUTIONS
2020 Gerlic Mordechay, PhD Tel Aviv University, Israel
RESEARCH TOPICS
Cell death mechanisms in the liver pathophysiology of alpha-1 antitrypsin-deficiency
2020 Patrick Geraghty, PhD
2020 Lela Lackey, PhD
2020 Richard Sifers, PhD
State University of New York (SUNY)
University of North Carolina at Chapel Hill
Baylor College of Medicine
2020 Valerie Guoun-Evans, PhD Boston Medical Center Corporation
2020 Scott Gordon, PhD University of Kentucky Research Foundation
2020 Kylie Belchamber, PhD
2020 Derek Russell, MD
2020 Stefan Marciniak, MD, PhD
University of Birmingham, UK
Chemical activation of protein phosphatase 2A to treat alpha-1 antitrypsin deficiency
Developing an accurate model of a-1-antitrypsin protein expression through RNA structure
Early onset end-stage liver disease parameters and model generation
Edited stem cell-based therapy with modified mRNA for AATD-associated liver disease
High Density Lipoprotein Targeting Protease Inhibitors for Preservation of Lung Function
Investigating macrophage phenotype and function in alpha- 1 antitrypsin deficiency
2020 Morten Dahl, MD, PhD
2020 Lynn Fussner, MD
2020 Nicola Brunetti-Pierri, MD
2020 Ross Edgar, MRes
University of Alabama at Birmingham
University of Cambridge, UK
Zealand University Hospital, Denmark
The Ohio State University
Telethon Institute of Genetics and Medicine, Italy
University of Birmingham, UK
Neutrophil-elastase positive exosomes and emphysema in alpha-1 antitrypsin deficiency
Probing biophysical changes in the endoplasmic reticulum during a1-antitrypsin deficiency
Risk of Cardiovascular Disease in Persons with Alpha-1-Antitrypsin ZZ Deficiency
Role of alpha-1 antitrypsin in anti-PR3 positive vasculitis
Role of JNK/c-JUN and CHOP pathways in liver disease induced by mutant Z-AAT
The development of a disease specific patient reported outcome in AATD
YEAR GRANTEES
2020 Robert Foronjy, MD
INSTITUTIONS
State University of New York (SUNY)
RESEARCH TOPICS
The Influence of A1AT on HuR Translocation and Airway Epithelial Cell Senescence
2020 Riccardo Ronzoni, PhD
2021 Andrew Wilson, MD
2021 Paul Ellis, MBChB
2021 Monica Goldklang, MD
University College London, UK
Boston University
University of Birmingham, UK
Columbia University
2021 Jeanine D'Armiento, MD, PhD Columbia University
2021 Keith Robertson, PhD Mayo Clinic
2021 Monica Goldklang, MD Columbia University
2021 Nunzia Pastore, PhD
2021 Richard Sifers, PhD
2021 Craig P. Hersh, MD, MPH
Telethon Institute of Genetics and Medicine, Italy
Baylor College of Medicine
Brigham and Women's Hospital
2021 Nazli Khodayari, PhD University of Florida
Z alpha-1antitrypsin polymers: kinetics of intracellular accumulation and secretion
Alpha-1 Foundation CRC Registry Data Transfer
Cardiovascular outcomes and phenotypes in pulmonary exacerbations of alpha-1 antitrypsin
Columbia University Alpha-1 Foundation Clinical Resource Center Physician Assistant
Direct effect of mutant alpha-1 anti-trypsin on the lung
Discovery and validation of non-invasive epigenetic biomarkers for AATD liver disease
In vivo functional imaging in alpha-1 antitrypsin deficiency
Investigating the effects of mutant a1-antitrypsin on liver cell fate and HCC development
Investigation of infantile endstage liver disease factors
Is COPD in Alpha-1 Antitrypsin MZ carriers the same as COPD in noncarriers?
Novel biomarkers for alpha 1antitrypsin mediated liver disease in circulating exosomes
2021 Bibek Gooptu, MD, PhD
University of Leicester, UK
Structural studies of immunomodulation in alpha1-antitrypsin
YEAR GRANTEES
2021 Maurizio Molinari, PhD
INSTITUTIONS
Fondazione per l'Istituto di Ricerca in Biomedicina Bellinzona, Switzerland
2021 Phillip Bird, PhD Monash University, Australia
RESEARCH TOPICS
The role of ER-to-lysosomeassociated degradation in clearance of polymerogenic ATZ
Use of transgenic zebrafish to identify modulators of Zantitrypsin induced pathology
2022 Jungnam Lee, PhD University of Florida
2022 John Rotondo, PhD University of Ferrara, Italy
2022 Emer Reeves, PhD The Royal College of Surgeons in Ireland
2022 Scott Gordon, PhD University of Kentucky Research Foundation
2022 Stefan Marciniak, MD, PhD University of Cambridge, UK
2022 Karina Serban, MD National Jewish Health
2022 Annamaria Fra, PhD University of Brescia, Italy
2022 Daniel Anderson, PhD Massachusetts Institute of Technology
2022 Lela Lackey, PhD Clemson University
2022 Juncheng Wei, PhD Northwestern University
A high concentration of adefensins impairs macrophage differentiation and function
Alpha-1 antitrypsin protein (AAT) as a possible marker of disease progression in COVID-19 patients
C3d: a key driver of inflammation in patients with alpha-1 antitrypsin deficiency
High Density Lipoprotein Targeting Protease Inhibitors for Preservation of Lung Function
Investigating the role of alpha-1-antitrypsin solidification in disease
Mannose-Binding-Lectin function in Alpha-1 deficiency with Mycobacteria pulmonary disease
Molecular bases of alpha-1antitrypsin functional deficiency
Prime editing therapy for alpha-1 antitrypsin deficiency
Regulation of A1AT expression via nuclear retention of SERPINA1 mRNA
Role of HRD1-METTL14 axis in alpha 1-antitrypsin deficiency induces liver disease
YEAR GRANTEES
2022 Stefanie Krick, MD, PhD
2022 Sheikh Tamir Rashid, MD, PhD
2023 Tomás Carroll, PhD
INSTITUTIONS
The University of Alabama at Birmingham
Imperial College of Science, Technology and Medicine, UK
Royal College of Surgeons in Ireland
RESEARCH TOPICS
Targeting Mucociliary Clearance Pathways in Alpha 1 Antitrypsin Deficiency
The role of LRRK2 in Alpha-1 Antitrypsin Deficiency
A Family Affair - Clarifying the Risk of Lung Disease in ZZ AATD
2023 Monica Goldklang, MD
Columbia University
2023 Jarrett Morrow, PhD
Brigham and Women's Hospital, Inc.
2023 Valerie Gouon-Evans, PhD Boston Medical Center Corporation
Alterations in inflammation and proteases during acute exacerbations of COPD in AATD
Blood and lung microbiome in alpha-1 antitrypsin deficiency
Engineered and edited patient-derived iPSC for AATD-associated liver disease cell therapy
2023 Igor Barjaktarevic, MD
2023 Francesco Annunziata, PhD
David Geffen School of Medicine at University of California Los Angeles
Telethon Institute Of Genetics And Medicine, Italy
2023 Brian Hobbs, MD Brigham and Women's Hospital, Inc.
2023 Monica Goldklang, MD Columbia University
Exploring the role of Nasal Transcriptome in bioprofiling Alpha-1 Antitrypsin Deficiency
Identification and modulation of local and systemic environmental factors in AATD
Inflammatory Protein Biomarkers of Reduced Lung Function in AATD
Longitudinal evaluation of lung disease progression in PiMZ patients
2023 Joseph Kaserman, MD Boston University
2023 Pasquale Piccolo, PhD
2023 Lisa Cabrita, PhD, BSc
Telethon Institute of Genetics and Medicine Italy
University College London, UK
Mechanisms of Hepatic Heterogeneity and ATF6
Mediated Metabolic Dysfunction in AATD
Mitochondrial dysfunction in a1-antitrypsin deficiencyassociated liver disease
Modulating the cotranslational misfolding and polymerisation of antitrypsin
YEAR GRANTEES
2023 Mike Wells, MD
INSTITUTIONS
University of Alabama at Birmingham
RESEARCH TOPICS
Molecular Profiling AATD Respiratory Specimens: A Pilot
2023 Shah Hussain, PhD
University of Alabama at Birmingham
2023 Georgios Sophocleous, PhD University College London, UK
Severity and progression of airway dropout in AAT knockout transgenic ferret model of COPD
Structural and biophysical dissection of the alpha-1 antitrypsin polymerisation pathway
2024 Ariel Curiale, PhD
Brigham and Women's Hospital, Inc.
2024 Emer Reeves, PhD Royal College of Surgeons in Ireland
2024 Carmine Settembre, PhD Fondazione Telethon ETS
AI Approaches to Define Emphysema Progression Risk in PiMZ and PiMS Heterozygous Subjects
Exploring Pro-Resolving Lipid Complexes to Realize the Full Therapeutic Impact of Alpha1
Exploring the Role of FAM134B-MEDIATED ERPHAGY in Alpha-1 Antitrypsin Deficiency
2024 Richard Sifers, PhD Baylor College of Medicine Identification of ESLD Prognostic Indicators
2024 Adel El Boueiz, MD
Brigham and Women's Hospital, Inc
2024 Jungnam Lee, PhD University of Florida
Imaging and Multi-omics Analyses of Emphysema Patterns in MM and MZ smokers
Mechanisms of a-Defensins Mediated Bacterial Infection in AATD Individuals
2024 Lela Lackey, PhD Clemson University
2024 James Irving, PhD University College London
2024 Nunzia Pastore, PhD Fondazione Telethon ETS
Misregulation of Polyadenylation during StressContributes to A1AT Deficiency Phenotypes
Rational Design of Better Diagnostic Reagents
Revealing the Role of Lysosomes in the Pathology of the AATD-Related Liver Disease
YEAR GRANTEES
INSTITUTIONS
2024 Bibek Gooptu, MD, PhD University of Leicester, UK
2025 Mark Murphy, PhD Royal College of Surgeons in Ireland
2025 Kristin Hudock, MD University of Cincinnati
2025 Emily Moser, PhD University of Florida
2025 Florian Rosenberger, PhD Max Planck Institute of Biochemistry
2025 Francesca Polverino, MD, PhD Baylor College of Medicine
2025 Konstantinos Thalassinos, PhD University College London
2025 Shah Hussain, PhD University of Alabama at Birmingham
2025 Sheikh Tamir Rashid, MD, PhD
Imperial College of Science, Technology and Medicine
2025 Devipriya Harinath, PhD Columbia University
RESEARCH TOPICS
Structural Studies of Misfolded and Polymeric Alpha1-Antitrypsin in ERAD and ERLAD
A Detailed Study of Lung Immune Cell Outcomes in AATD
A Novel Strategy to Deliver Intrapulmonary AAT & Limit Lung Destruction in Models of AATD
Alpha-1 Antitrypsin Promotes Vaccine Antibody Responses
Alpha-1 Hepatocyte Dynamics: A Single-Cell and Spatial Proteomics Study
B Cell Adaptive Immune Profile in A1AT DeficiencyAssociated Emphysema
Cellular Effects of A1AT Aggregation with Single-Cell and Crosslinking Proteomics
Characterizing RASCs in AATDeficient Ferrets: Implications for COPD and Distal Airway Remodeling
Deciphering the Molecular Landscape in Alpha-1 Antitrypsin Deficiency Liver Disease
Diversity of SERPINA1 Mutations as Reflected in an Indian Population
2025 Cheryl Pirozzi, MD University of Utah
2025 Vera Khodzhaeva, PhD
Cambridge Institute for Medical ResearchUniversity of Cambridge
Effect of Environmental Exposures in Alpha-1 Antitrypsin Deficiency in the Alpha-1 Biomarker Consortium
FGF21 and Cellular Homeostasis in Alpha1Antitrypsin Deficiency
YEAR GRANTEES
INSTITUTIONS
2025 Suzanne Roche, MB, BCh, BAO Royal College of Surgeons in Ireland
RESEARCH TOPICS
Genetic Discrimination –Tackling a Growing Issue in Alpha-1 Antitrypsin Deficiency
2025 Huiliang Wang, PhD
2025 Leonard Riley, MD
2025 Rhiannon Werder, Ph.D
The University of Texas at Austin
University of Kansas Medical Center Research Institute, Inc
Murdoch Children's Research Institute
2025 Camila Lopes-Ramos, PhD Brigham and Women's Hospital, Inc
2025 Jorge Lascano, MD
University of Florida
Genetic Engineered Exosomes for Efficient DNA Delivery for Alpha-1 Antitrypsin Deficiency
Impact of a Multicenter Best Practice Alert to Improve AATD Testing and Detection
Investigating the Cellular and Molecular Mechanisms of Respiratory Infections in AATD
Multi-omic Sex Differences in Alpha 1 Antitrypsin Deficiency Associated COPD
Nicotine as a Cause of Airway Inflammation and Lung Emphysema in a Novel AATD Mouse Model
2025 Christine Wendt, MD
2025 Karen McDonald, PhD
Center for Veterans Research and Education
University of California Davis
2025 Valerie Gouon-Evans, PhD Boston Medical Center Corporation
2025 Hirofumi Kiyokawa, MD, PhD Boston University
2025 Valentina Schiano, PhD
Fondazione Telethon ETS
2025 Gerry McElvaney, MD, DSc Royal College of Surgeons in Ireland
Prevalence of Alpha 1 Antitrypsin Deficiency amongst Veterans
Production and Characterization of a Biobetter Recombinant AATFc Therapeutic Protein
Promoting Progenitor-Driven Liver Regeneration as an AATD-Associated Liver Disease Therapy
Regeneration of Lung Epithelial Stem Cell Compartments in a Novel ZAAT Mouse Model
Targeting Inflammation as Therapeutic Approach for AATD
The Risk of Lung Disease in People with MZ Alpha-1 Antitrypsin Deficiency
YEAR GRANTEES
INSTITUTIONS
2026 María Magallón, PhD University of Florida
2026 Emily Moser, PhD
2026 Craig Hersh, MD, MPH
2026 Emma Leacy, PhD
2026 Pasquale Piccolo, PhD
University of Florida
Brigham and Women's Hospital, Inc.
RESEARCH TOPICS
AAT Deficiency Impairs WNT Signaling and Leads to Inefficient Epithelial Cell (AT2) Repair
Alpha-1 Antitrypsin Promotes Vaccine Antibody Responses
Characterizing the Lung Inflammatory Milieu in Alpha-1 Antitrypsin Deficiency
2026 Debananda Gogoi, PhD
2026 Vickram Tejwani, MD
Royal College of Surgeons in Ireland
Fondazione Telethon ETS
Royal College of Surgeons in Ireland
Comprehensive Lipidomic Profiling of Bronchoalveolar Lavage Fluid (BALF) in AATD
Development of RNA Aptamers Inhibiting Polymerization of Mutated Z Alpha-1-Antitrypsin
Exploring the Role of MZB1 in Alpha-1 Antitrypsin Deficiency and Disease Pathogenesis
Cleveland Clinic Foundation Exposures Among Those with SERPINA1 Gene Variants
2026 Jingzhou Zhang, MD, MPH Boston University
2026 David LaFon, MD University of Alabama at Birmingham
2026 Shubham Kesarwani, PhD Boston University
2026 Paul Ellis, MBChB, PhD University of Birmingham, UK
2026 Lisa Cabrita, PhD
University College London
Genetic and Proteomic Prediction and Pathways of COPD Risk in Alpha-1 Antitrypsin MZ
Genetic Variation in IgG as a Mechanism for Immune Deficiency and Exacerbations in AATD
Identify the Genetic Risk Modifiers of Hepatotoxicity in Alpha1-Antitrypsin Deficiency
Modeling Quality of Life in AATD: Predictive and Proteomics Insights
Molecular Studies of Antitrypsin's Folding and Polymerisation in the Endoplasmic Reticulum
YEAR GRANTEES
2026 Shunqing Liang, PhD
INSTITUTIONS RESEARCH TOPICS
University of Minnesota - Twin Cities
2026 Sandeep Bodduluri, PhD
2026 Emily van 't Wout, MD, PhD
2026 Lela Lackey, PhD
2026 Nilsson Holguin, PhD
2026 Maurizio Molinari, PhD
2026 Nunzia Pastore, PhD
2026 Leandro Soria, PhD
University of Alabama at Birmingham
Leiden University Medical Center
Clemson University
Icahn School of Medicine at Mount Sinai
Fondazione per l'Istituto di Ricerca in Biomedicina Bellinzona
Fondazione Telethon ETS
Fondazione Telethon ETS
Scientific Impact of A1F Funding:
Prime Editing Strategies to Address the Root Cause of Alpha-1 Antitrypsin Deficiency
Silent Zones of Disease in Alpha-1 Antitrypsin Deficiency
The Role of Polymers in Repair and Regeneration in AATD-Related Emphysema
Translation Regulation of SERPINA1 mRNA Controls A1AT Protein Expression
Treatment of Osteoporosis from Alpha-1 Antitrypsin Deficiency
Understanding the Molecular Mechanisms of Lysosomal Clearance of ATZ Polymers
Unveiling the Role of SOX9 in the Liver Pathology of AATD
Ureagenesis as a Novel Biomarker for AATD Liver Disease
A1F has developed a rigorous process, modeled on the The National Institutes of Health (NIH), to vet grant applications and ensure that our funds support the highest quality research. It is important that we measure the impact of A1F support to validate the efficacy of this approach. We can measure this impact in a variety of ways, including the metrics below:
NIH grant support resulting from A1F funding: NIH is historically the largest funder of biomedical research in the world. We encourage A1F-funded researchers to build on the findings they make with A1F support to apply for additional funding from the NIH. A1F investment of $48.9 million in investigator-initiated proposals from 1999-2025 has subsequently resulted in $732.8 million in funds from the federal government to our awardees, a return-on-investment of approximately $15 per dollar awarded.
Publications resulting from A1F funding: Dissemination of research findings is critical to advance scientific knowledge. A1F-funded investigators are strongly encouraged to publish findings they make with A1F support. From 2018-2025, A1F-funded investigators published 153 articles in scientific journals on all aspects of AATD.
Patents resulting from A1F funding: Research findings have the potential to identify mechanisms or develop techniques with potential therapeutic value. Patent activity is thus an additional measure of impact. Between 2001-2025, A1F funded investigators have filed 48 patent applications.
Impact on Clinical Trials:
A key aspect of our mission is to develop new treatments and ultimately a cure for patients with AATD. In the 5 years since the last impact report, the AAT therapeutic landscape has changed dramatically, with numerous drugs targeting a variety of mechanisms advancing to preclinical development or clinical trials. This evolution reflects a combination of increased understanding of cellular disease mechanisms together with technological advances, particularly in the ability to manipulate gene architecture and expression through a variety of approaches. Our community is fortunate that seminal advances in genetic targeting (collectively including Nobel prize-winning discoveries such as RNA interference and CRISPR, together with gene therapy and RNA editing) that can be applied to many genetic diseases are potentially therapeutically useful in AATD. The development of small molecules to assist in proper folding or stabilize misfolded AAT proteins has likewise shown promise as a novel class of potential therapeutics. Finally, alternative delivery approaches, dosing, and recombinant forms of AAT protein are in ongoing testing and could result in improved efficacy and quality of life for patients.
The rapid progress made in the application of emerging therapies to AATD is in no small part the result of A1F funding. A1F support laid the groundwork that made it possible to identify approaches that were likely to succeed, demonstrate efficacy in preclinical models, and is enabling their successful testing and application for patients suffering from AATD. Over a 25 year period, A1F-funded researchers have established a broad understanding of the disease, ranging from basic disease mechanisms to the clinical experience of affected patients.
This knowledge base is now being applied in many ways for trial design and implementation, from identifying which patients with AATD are most likely to benefit from specific therapeutic approaches to determining how to measure the success of drugs in development.
In addition to direct funding of research in the form of grant support, the A1F has invested significantly in infrastructure designed to facilitate and promote the success of the aforementioned clinical trials. This support includes:
The Alpha-1 Research Registry: The Alpha-1 Research Registry includes data from more than 4,000 individuals including >1,300 with severe AATD. In addition to its utility as a tool for investigators to address questions of natural history, the registry helps to connect patients with clinical studies that they may qualify for based on their demographic and clinical characteristics. Registry staff have been successful in helping to recruit Alphas to participate in ongoing clinical trials of emerging therapeutics.
The Therapeutic Development Network (TDN): To identify patients interested in participating in clinical trials and who live in proximity to clinical trial sites as a complement to the Alpha-1 Research Registry, the A1F created the TDN. The TDN consists of 20 centers across the US that have agreed to participate in upcoming clinical trials. Each site enrolls local patients and collects a set of data about each enrolled participant that includes the basic inclusion and exclusion criteria for most clinical trials. The resulting database is then a resource for identifying potential clinical trial participants across the country.
The Alpha-1 Biomarkers Consortium (A1BC): In order to design and execute clinical trials, industry partners need biomarkers that are established and recognized by the FDA to correlate with disease severity and progression. The A1BC is a consortium of A1F Clinical Resource Centers (CRCs) funded by the NIH and A1F that has enrolled > 270 severely deficient (ZZ) patients. These centers are collecting longitudinal data and biosamples from this cohort to develop the biomarkers that can then be used as clinical trial endpoints.
The DNA and Tissue Bank: Established in 2001, the bank includes a data repository together with plasma samples and genomic DNA from 2,849 participants, including 812 ZZ, 501 MZ, 88 SZ, 115 MS, and 342 rare alleles. This resource provides the ability to connect DNA sequence with disease phenotype and clinical characteristics and is a tool for addressing research questions about the genetic basis of AATD.
Looking Ahead:
As we look to the future, we see many reasons for optimism. Much of this optimism relates to the clinical trials that have recently started and are anticipated to start in the upcoming 24 months. To ensure that the promise of this moment is realized, A1F will take the following actions in the next 5 years:
Facilitate the success of clinical trials: To ensure the success of clinical trials, we will take several key steps: First, we will continue to support the A1BC and its efforts to identify radiologic and serum biomarkers associated with specific disease states that can similarly inform clinical trials. Second, we will continue to invest in the Alpha-1 Research Registry and the TDN. Finally, we will continue our partnership with the Critical Path Institute and our industry partners to establish endpoints that the FDA will embrace in clinical trials.
Increase detection of Alphas: It is estimated that only 15% of severely deficient patients with AATD have been identified. It is critical that we increase the detection of Alphas both to facilitate clinical trial enrollment and also to identify severely deficient patients earlier in the course of disease when they are more likely to benefit from treatment. To increase detection, we will continue our recent investment in AlphaDetect, a new non-profit subsidiary of A1F, that will lead a transformative initiative that unifies all community stakeholders – patients, healthcare providers, advocates, and industry partners – with a collective common purpose: to ensure no Alpha-1 patient is left undetected.
Invest in research infrastructure: By developing tools that facilitate the ability of researchers to ask questions, we can increase their ability to make discoveries that will benefit Alphas in the years to come. To do so, we will continue to build the natural history component of the Alpha-1 Research Registry to enhance its value for research purposes. We will likewise continue to build genetic data capabilities to facilitate the ability to connect genotypes to phenotypes and continue to invest in human capital through support for the careers of early-stage investigators to sustain a pipeline of scientific expertise in AATD. Finally, we will continue to fund cutting edge research that will produce discoveries that will enable development of the next generation of treatments for AATD.
Increase CRC availability to patients: To get the best care available, patients need access to physicians and allied health professionals with AATD expertise. To increase the availability of such expertise, we will continue to identify and cultivate physicians with AATD expertise, in particular those specializing in pediatric gastroenterology and adult gastroenterology. We will specifically work to increase the number of Clinical Resource Centers in areas of the country that are currently less well represented.
In summary, A1F is working on many fronts and will continue to do so to accomplish the best possible outcomes for Alphas to achieve our mission of finding a cure for Alpha-1.
The Alpha-1 Foundation (A1F) is committed to finding a cure for Alpha-1 Antitrypsin Deficiency (Alpha-1) and to improving the lives of people affected by Alpha-1 worldwide.
ALPHA1.ORG
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