Advances in the Treatment of Alpha1-antitrypsin Deficiency
In animal studies, intramuscular injections of recombinant adeno-associated virus serotype-2 (rAAV2) containing the normal AAT gene were shown to be safe and result in significant expression and increased serum levels of AAT.78,79
In the first Phase I trial of
The vector DNA sequence was detected in blood by PCR on days one and three in most subjects receiving the higher doses. However, only a low level of transgenic M-AAT was transiently detected in the serum of one subject.
intramuscular injections with this vector on 12 subjects with PiZZ AATD, four different doses were tested and no significant side effects were observed.80
In order to improve efficiency, the same researchers used a different carrier, namely a rAAV serotype 1 capsid, which had a similar safety profile and a more sustained AAT expression in mice.78,81
There are promising animal data in transgenic mice suggesting that such approach can reconstitute the liver’s ability to produce normal human AAT.83
Bone marrow cells where isolated and infected with Lenti-CB-hAAT, rAAV1-CB-hAAT, and rAAV8-CB-hAAT. After re-injection, significant levels of transgenic product h-AAT were detected in liver and serum, especially with the rAAV8 vector. Studies in humans have not been reported.
Conclusions
AATD continues to be a very challenging condition. Screening and early detection continues to be crucial as prompt diagnosis may lead to more effective risk factor modifications that may prevent the development of lung disease.
In this study,
three different dose groups were tested in nine PiZZ individuals. Sustained, but still subtherapeutic, expression of M-AAT was observed for at least one year in two subjects and 90 days in a third, who received the highest dose. T-cell immune responses did not cause the complete elimination of the vector.82
These trials are the basis for continued explorations of the possibility of gene therapy for AATD. The safety and feasibility of the injections along with a controlled immune response is encouraging. Gene therapy trials are under way to try to maintain a constant production of AAT at protective levels. Current trials aim to discover whether higher dosing or more injection sites provide higher and sustained AAT expression.
Stem Cell Therapy
Stem cells have been used in patients in need of for cell replacement therapy (i.e., bone marrow transplantation in cancer patients). Stem cells have the ability to differentiate into different, functional cells with normal gene expression. In AATD, the goal is to establish new hepatocytes that produce normal AAT.
1. de Serres FJ, Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: Summary of an analysis of published genetic epidemiologic surveys, Chest, 2002;122:1818–29.
2. McElvaney NG, Stoller JK, Buist AS, et al., Baseline characteristics of enrollees in the national heart, lung and blood institute registry of alpha 1-antitrypsin deficiency. Alpha 1-antitrypsin deficiency registry study group, Chest, 1997;111:394–403.
3. Sveger T, Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants, N Engl J Med, 1976;294:1316–21.
4. Yang P, Wentzlaff KA, Katzmann JA, et al., Alpha 1-antitrypsin deficiency allele carriers among lung cancer patients, Cancer Epidemiol Biomarkers Prev, 1999;8:461–5.
5. Eriksson S, Alpha 1-antitrypsin deficiency and liver cirrhosis in adults. An analysis of 35 swedish autopsied cases, Acta Med Scand, 1987;221:461–7.
6. de Serres FJ, Blanco I, Fernandez-Bustillo E, Genetic epidemiology of Alpha1-antitrypsin deficiency in north america and australia/new zealand: Australia, canada, new zealand and the united states of america, Clin Genet, 2003;64:382–97.
7. Silverman EK, Miletich JP, Pierce JA, et al., Alpha-1- antitrypsin deficiency. High prevalence in the st. Louis area determined by direct population screening, Am Rev Respir Dis, 1989;140:961–6.
8. Lieberman J, Winter B, Sastre A, Alpha 1-antitrypsin pi-types in 965 copd patients, Chest, 1986;89:370–3.
9. Stoller JK, Sandhaus RA, Turino G, et al., Delay in diagnosis of alpha1-antitrypsin deficiency: A continuing problem, Chest, 2005;128:1989–94.
10. Campos MA, Wanner A, Zhang G, Sandhaus RA, Trends in the diagnosis of symptomatic patients with alpha1- antitrypsin deficiency between 1968 and 2003, Chest, 2005;128:1179–86.
11. Campos MA, Alazemi S, Zhang G, et al., Effects of a disease management program in individuals with Alpha1-antitrypsin deficiency, COPD, 2009;6:31–40.
12. Parr DG, Stoel BC, Stolk J, Stockley RA, Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment, Am J Respir Crit Care
Med, 2004;170:1172–8.
13. American thoracic society/european respiratory society statement: Standards for the diagnosis and management of individuals with Alpha1-antitrypsin deficiency, Am J Respir Crit Care Med, 2003;168:818–900.
14. Perlmutter DH, Cole FS, Kilbridge P, et al., Expression of the alpha 1-proteinase inhibitor gene in human monocytes and macrophages, Proc Natl Acad Sci U S A, 1985;82:795–9.
15. Cichy J, Potempa J, Travis J, Biosynthesis of alpha1- proteinase inhibitor by human lung-derived epithelial cells, J Biol Chem, 1997;272:8250–5.
16. Wilczynska M, Fa M, Karolin J, et al., Structural insights into serpin-protease complexes reveal the inhibitory mechanism of serpins, Nat Struct Biol, 1997;4:354–7.
17. Petrache I, Fijalkowska I, Medler TR, et al., Alpha1-antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis, Am J Pathol, 2006;169:1155–66.
18. Ikari Y, Mulvihill E, Schwartz SM, Alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and alpha 2-macroglobulin are the antiapoptotic factors of vascular smooth muscle cells, J Biol Chem, 2001;276:11798–803.
19. Daemen MA, Heemskerk VH, van't Veer C, et al., Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation, Circulation, 2000;102:1420–6.
20. Nita I, Hollander C, Westin U, Janciauskiene SM, Prolastin, a pharmaceutical preparation of purified human alpha 1-antitrypsin, blocks endotoxin-mediated cytokine release, Respir Res, 2005;6:12.
21. Jie Z, Cai Y, Yang W, et al., Protective effects of alpha 1-antitrypsin on acute lung injury in rabbits induced by endotoxin, Chin Med J (Engl), 2003;116:1678–82.
22. Bucurenci N, Blake DR, Chidwick K, Inhibition of neutrophil superoxide production by human plasma alpha 1-antitrypsin, FEBS Lett, 1992;300:21–4.
23. Janciauskiene S, Larsson S, Larsson P, et al., Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin, Biochem Biophys Res Commun, 2004;321:592–600.
24. Churg A, Dai J, Zay K, et al., Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, rs113456, have similar
Although specific data are scarce, subjects with AATD and lung disease should be treated according to COPD guidelines with drugs such as long-acting bronchodilators and inhaled steroids. Disease management programmes have been shown to be effective in improving quality of life and healthcare utilisation in this population. There is an imperative need for better targeting of the group of patients that will mostly benefit from augmentation therapy as well as trials a need for determining AAT’s optimal dosage.
Several potential therapeutic strategies exist to target the different pathophysiological mechanisms of the disease, for both the liver and lung manifestations. To augment AAT levels, these strategies include alternate routes of administration (inhaled), gene therapy and stem cell therapy. To decrease intracellular AAT polymerisation, AAT secretion and the formation of extracellular AAT polymers, strategies that block polymerisation with small molecules or increase autophagic degradation are under way with promising results. These new strategies will need to be validated in larger clinical trials. n
acute anti-inflammatory effects, Lab Invest, 2001;81:1119–31.
25. Janciauskiene S, Nita I, Subramaniyam D, et al., Alpha 1-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro, Am J Respir Cell Mol Biol, 2008;39:631–7.
26. Lomas DA, Evans DL, Finch JT, The mechanism of z alpha 1- antitrypsin accumulation in the liver, Nature, 1992;357:605–7.
27. Teckman JH, Perlmutter DH, Retention of mutant alpha 1-antitrypsin z in endoplasmic reticulum is associated with an autophagic response, Am J Physiol Gastrointest Liver Physiol, 2000;279:G961–74.
28. Teckman JH, Gilmore R, Perlmutter DH, Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin z in the endoplasmic reticulum, Am J Physiol Gastrointest Liver Physiol, 2000;278:G39–48.
29. Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH, Accumulation of mutant alpha1-antitrypsin z in the endoplasmic reticulum activates caspases-4 and -12, nfkappab, and bap31 but not the unfolded protein response, J Biol Chem, 2005;280:39002–15.
30. Hultcrantz R, Mengarelli S, Ultrastructural liver pathology in patients with minimal liver disease and alpha 1-antitrypsin deficiency: A comparison between heterozygous and homozygous patients, Hepatology, 1984;4:937–45.
31. Dafforn TR, Mahadeva R, Elliott PR, et al., A kinetic mechanism for the polymerization of alpha1-antitrypsin, J Biol Chem, 1999;274:9548–55.
32. Taggart C, Cervantes-Laurean D, Kim G, et al., Oxidation of either methionine 351 or methionine 358 in alpha 1- antitrypsin causes loss of anti-neutrophil elastase activity, J Biol Chem, 2000;275:27258–65.
33. Demeo DL, Sandhaus RA, Barker AF, et al., Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency, Thorax, 2007;62:806–13.
34. Lomas DA, Elliott PR, Sidhar SK, et al., Alpha 1-antitrypsin mmalton (phe52-deleted) forms loop-sheet polymers in vivo. Evidence for the c sheet mechanism of polymerization, J Biol Chem, 1995;270:16864–70.
35. Parmar JS, Mahadeva R, Reed BJ, et al., Polymers of alpha(1)- antitrypsin are chemotactic for human neutrophils: A new paradigm for the pathogenesis of emphysema, Am J Respir Cell Mol Biol, 2002;26:723–30.
36. Mahadeva R, Atkinson C, Li Z, et al., Polymers of z
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