Alpha-1 antitrypsin deficiency and recombinant protein sources with focus on plant sources: Updates, challenges and perspectives

Matthew J McNulty; David Z Silberstein; Brooks T Kuhn; Hal S Padgett; Somen Nandi; Karen A McDonald; Carroll E Cross

doi:10.1016/j.freeradbiomed.2020.11.030

Alpha-1 antitrypsin deficiency and recombinant protein sources with focus on plant sources: Updates, challenges and perspectives

Free Radic Biol Med. 2021 Feb 1:163:10-30. doi: 10.1016/j.freeradbiomed.2020.11.030. Epub 2020 Dec 3.

Authors

Matthew J McNulty¹, David Z Silberstein¹, Brooks T Kuhn², Hal S Padgett³, Somen Nandi⁴, Karen A McDonald⁴, Carroll E Cross⁵

Affiliations

¹ Department of Chemical Engineering, University of California, Davis, CA, USA.
² Department of Internal Medicine, University of California, Davis, CA, USA; University of California, Davis, Alpha-1 Deficiency Clinic, Sacramento, CA, USA.
³ Novici Biotech LLC, Vacaville, CA, USA.
⁴ Department of Chemical Engineering, University of California, Davis, CA, USA; Global HealthShare Initiative®, University of California, Davis, CA, USA.
⁵ Department of Internal Medicine, University of California, Davis, CA, USA; University of California, Davis, Alpha-1 Deficiency Clinic, Sacramento, CA, USA; Department of Physiology and Membrane Biology, University of California, Davis, CA, USA. Electronic address: cecross@ucdavis.edu.

PMID: 33279618
DOI: 10.1016/j.freeradbiomed.2020.11.030

Abstract

Alpha-1 antitrypsin deficiency (A1ATD) is an autosomal recessive disease characterized by low plasma levels of A1AT, a serine protease inhibitor representing the most abundant circulating antiprotease normally present at plasma levels of 1-2 g/L. The dominant clinical manifestations include predispositions to early onset emphysema due to protease/antiprotease imbalance in distal lung parenchyma and liver disease largely due to unsecreted polymerized accumulations of misfolded mutant A1AT within the endoplasmic reticulum of hepatocytes. Since 1987, the only FDA licensed specific therapy for the emphysema component has been infusions of A1AT purified from pooled human plasma at the 2020 cost of up to US $200,000/year with the risk of intermittent shortages. In the past three decades various, potentially less expensive, recombinant forms of human A1AT have reached early stages of development, one of which is just reaching the stage of human clinical trials. The focus of this review is to update strategies for the treatment of the pulmonary component of A1ATD with some focus on perspectives for therapeutic production and regulatory approval of a recombinant product from plants. We review other competitive technologies for treating the lung disease manifestations of A1ATD, highlight strategies for the generation of data potentially helpful for securing FDA Investigational New Drug (IND) approval and present challenges in the selection of clinical trial strategies required for FDA licensing of a New Drug Approval (NDA) for this disease.

Keywords: Alpha-1 antitrypsin (A1AT); Alpha-1 antitrypsin deficiency (A1ATD); Gene therapy; Molecular pharming; Recombinant A1AT.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

MeSH terms

Humans
Lung Diseases*
Pulmonary Emphysema*
Recombinant Proteins / genetics
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency* / drug therapy
alpha 1-Antitrypsin Deficiency* / genetics

Substances

Recombinant Proteins
alpha 1-Antitrypsin