Therapeutic potential of alpha-1 antitrypsin in human disease

1. AAT deficiency

AAT deficiency is an autosomal codominant hereditary disorder that causes defective AAT production, which leads to decreased AAT activity in both the blood and lungs as well as the accumulation of excessive, non-functional AAT protein in liver cells [6,7]. It is often subject to delayed diagnosis because (1) Asymptomatic AAT level reductions, as low as 85% of normal circulation levels in healthy individuals, can be easily detected in random assessments [8]; (2) Biochemical analyses, such as western blotting and enzymelinked immunosorbent assays, can misinterpret the inactivated form of AAT as the functional form [9]; and (3) Relative functional deficiency can exist as shown through the failure of AAT under physiological conditions [10]. AAT deficiency affects 1/4,000–1/5,000 people and 1%–2% of all chronic obstructive pulmonary disease (COPD) patients in the United States [11]. The main clinical conditions associated with AAT deficiency include COPD and liver cirrhosis. Nevertheless, it has broad spectrum pulmonary and extrapulmonary manifestations leading to pulmonary emphysema or COPD in adults as well as various liver diseases, panniculitis, pancreatitis, glomerulonephritis, and vascular diseases in a minority of children and adults. It is occasionally associated with less common problems such as fibromyalgia, mood disorders, and intense creative energy [12-15]. The development of COPD is related to a decrease in the function or levels of AAT in the serum, which renders neutrophil elastase (NE) free to break down elastin and causes decreased elastin levels. The detected normal range of AAT in the serum varies because of variability in commercial standards. Based on the onset of emphysema, an abnormal AAT value is 11 μM or lower [16-18].

The only safe treatment available for emphysema due to AAT deficiency is intravenous AAT augmentation. However, the efficacy of this treatment remains controversial. Because the incidence is usually low and disease progression is slow, it is impractical to conduct appropriate studies to evaluate the rate of lung function decline and reservation [19-27].

2. Type 2 diabetes

Type 2 diabetes is a metabolic, chronic inflammatory disease. Diabetic inflammation results in local and systemic insulin resistance, which causes increases in circulating glucose levels. To compensate for increased insulin resistance, the functional β-cell mass first swells to induce hyperinsulinemia. Then, local and systemic inflammatory reactions destroy the resident islet β-cell mass. Blocking the inflammatory pathway can restore the insulin response [10].

The mechanism of action of AAT in type 2 diabetes is unclear, but AAT is known to protect pancreatic β-cells from apoptosis by inhibiting caspase-3 [28,29]. Recent studies have shown that the proportion of individuals with low AAT levels (1.0 mg/mL or lower) was 50% higher among diabetic adult patients than the non-diabetic population [30]. The administration of AAT to patients with type 2 diabetes may reduce the severity of the disease.

3. Type 1 diabetes

Type 1 diabetes, known as juvenile diabetes or insulindependent diabetes, is a progressive condition caused by little or no insulin production by the pancreatic islet β-cells [31]. It can be caused by numerous factors, including genetics, infection, or the destruction of the pancreatic islet β-cells by autoreactive T cells [32]. The control of blood glucose levels and the reduction of diabetic complications are critically linked to the protection of pancreatic β-cells. Despite decades of advanced study, the ultimate treatment for this disease has not been determined.

However, recent studies on AAT have indicated that controlling inflammation and immune responses aids pancreatic β-cell function through the down-modulation of interleukin (IL)-1β and other pro-inflammatory cytokines [33]. IL-1β is known to be harmful to insulin-producing cells. Although the levels of circulating AAT in type 1 diabetic patients may appear to be within normal ranges, AAT function is impaired as a result of extensive non-enzymatic glycation, suggesting that functional AAT levels may play a role in disease progression [34-36]. In the nonobese diabetic (NOD) mouse model, which is the autoimmune animal model for type 1 diabetes, serum AAT levels are only half those found in the majority of wild type mice [37]. NOD mice recover to normoglycemia 14 days after AAT treatment, and NOD mice that overexpress AAT have reduced insulitis and do not develop hyperglycemia [38]. In addition, the administration of clinical-grade human AAT to mice with chemically induced diabetes promotes pancreatic islet allograft survival and cytoprotective effects [29].

AAT therapy (80 mg/kg/dose) was reported to be beneficial to β-cell function in adult type 1 diabetic patients [39]. Rachmiel et al. [40] reported that AAT treatment was feasible, without serious adverse complications, and improved glycemic control and serum peak c-peptide levels in pediatric patients with recently diagnosed autoimmune diabetes during a 37-week study period. Currently, 2 phase III, double-blind, randomized, placebocontrolled trials enrolling type 1 diabetic patients at the time of onset are underway [40], and research into the function of AAT in diabetes is ongoing (Table 1).

Table 1.

In vivo and in vitro biological activities of AAT on diabetes

4. Chronic obstructive pulmonary disease

COPD, the third leading cause of death in the world, can have a variety of causes, with cigarette exposure the most common [41]. The typical progression of COPD results in alveolar destruction, coughing/chronic mucus production, chronic inflammation, and irreversible airflow limitation characterized by protease imbalance and progressive loss of lung function [42]. COPD treatments include inhaled bronchodilators, steroids, and longterm oxygen therapy. However, there are no effective therapies to reverse COPD.

Although AAT concentrations are within the normal range in COPD patients, their protease/antiprotease balances have been broken [43]. COPD airways present increased NE activity compared to that in healthy airways, resulting in exacerbation of mucus dehydration and reduction of mucociliary clearance [44]. AAT can minimize pulmonary damage through suppression of NE activity. The theoretical, potential therapeutic effects of AAT therapy include the neutralization of serine proteinases from neutrophils, the reduction of leukotriene B4 released from macrophages and suppression of neutrophil chemotaxis [1]. One of the main disadvantages of the AAT therapy is that intravenous AAT arrives at the lung in a relatively inactive state. To overcome this obstacle, direct aerosol delivery to the airway has been introduced and short-term studies have shown improvements in protection of the lung epithelium and in lower respiratory anti-NE defenses [45]. To date, the inhaled AAT therapy has shown biochemical efficacy and safety in human studies [46]. In addition, the other recombinant AAT studies as stem cell therapy and gene therapy are underway [1]. However, a long-term follow-up study is needed for this methodology.

5. Cystic fibrosis

Cystic fibrosis (CF), caused by the mutation of CF transmembrane conductance regulator, progresses from childhood. CF patients have various pulmonary symptoms, such as the production of thick mucus, chronic airway infection, and inflammation, which lead to decreased pulmonary function and early death [47]. In a CF lung, neutrophil counts are elevated over those in a healthy lung and secreted NE leads to the destruction of the defense mechanisms of the lung against infection and inflammation. Thus, in CF, the treatment focus is on decreasing neutrophil hyperactivation and counteracting the effects of NE on the lung. To inhibit NE in the lung during CF progression, early studies have focused on the augmentation of systemic AAT levels by intravenous injection [48]. Recently, a randomized, double-blind, placebo-controlled phase 2a study in CF patients has been further performed to evaluate the safety of 100 or 200 mg of inhaled AAT once daily for 3 weeks in 30 adult subjects and reported that inhalation is safe and well tolerated [49]. Further multiple studies have demonstrated that AAT administered by inhalation can control neutrophil function and NE levels in a dose-dependent fashion as well as inflammation in the lung [48]. However, many obstacles still remain in applying AAT in CF since mixed results have been observed depending on the devices used as well as lung condition and NE concentration of patients.

6. Others

Graft-versus-host disease (GVHD), which remains a major problem in allogeneic hematopoietic cell transplantation, is ameliorated by the inhibition of IL-1 production/activity, inhibition of proteinase 3-related IL-32 activation, and increased release of IL-1 receptor antagonist and IL-10 in animal models [1]. In a human study, AAT was well-tolerated and demonstrated efficacy in the treatment of steroid-refractory severe acute GVHD [50]. The injection of human AAT or the production of adenoviral plasmid-derived, circulating human AAT can delay rheumatoid arthritis development in a mouse model via the inhibition of IL-6, IL-1β, and TNF-α along with the neutralization of serine proteinases and aggrecanase-1 from neutrophils [51]. Recently published preclinical and clinical reports have shown that AAT is related not only to infectious diseases, but also to inflammatory bowel disease, acute myocardial infarction, and connective tissue/rheumatoid diseases [10]. In addition, recent animal studies using the colitisassociated colon cancer mouse model demonstrated that AAT treatment resulted in a significant inhibition of tumor incidence accompanying amelioration of colonic inflammation compared with controls, strongly suggesting therapeutic potential of AAT in colitis-associated colon cancer (personal communication with Dr. Q. Cai).