Alpha1antitrypsin Deficiency

Another lung disease that can potentially be treated with synthetic vectors is a-1-antitrypsin (AAT) deficiency. AAT defi

Figure 3 Theoretical strategy for achieving therapeutic levels of expression from synthetic vectors. Multiple dosing using a pDNA vector that confers sustained expression may lead to cumulative expression over time.

ciency is an autosomal recessive disorder caused by mutations in the gene encoding AAT, the principal antiprotease present in human plasma. AAT inhibits neutrophil elastase and thereby helps to protect the lung from destruction by this protease. Patients with low levels of AAT are susceptible to developing emphysema, and a subset also develops liver disease

One gene therapy strategy for AAT deficiency is to transduce the liver, the normal site of AAT synthesis. The AAT is then secreted into the circulation and taken up by the lung

(36). A second approach is to deliver the gene directly into the lumen of the lung, taking advantage of the ability of cationic lipid-DNA complexes to transduce the lung parenchyma. With this strategy lower but localized increases in AAT concentration may be as or more effective than elevating serum AAT levels. The levels of AAT required to be protective are not known, but in vitro studies have shown that small changes in AAT concentration can lead to relatively large alterations in neutrophil proteolytic activity (37).

A clinical trial was conducted on 5 patients with AAT deficiency (38). The cationic lipid formulation DOTMA-DOPE was complexed with a pDNA vector expressing AAT. As in the CF trials, the nose was used as a surrogate for the lung, and complex was applied to one nostril with the other nostril serving as the control. AAT levels in the nasal lavage fluid increased about 2-fold over baseline, peaking at day 5 and returning to near baseline levels by day 14. Although the peak levels of AAT reached only one-third of the normal mean, there appeared to be an anti-inflammatory effect from the treatment as evidenced by a slight but statistically significant decrease in IL-8 levels in the nasal lavage fluid. In contrast, intravenous delivery of AAT protein resulted in levels of AAT in the nasal lavage fluid within the normal range, but IL-8 levels did not decrease. These results bolster the contention that certain critical regions (e.g., the interstitial spaces between cells) are more easily accessible using local ized gene transfer rather than intravenous delivery of protein (38).

If these studies are to progress to the lung, the same safety issues as in CF will need to be addressed, namely the acute inflammatory response from aerosolized cationic lipid-pDNA complex. Also as in CF, the endpoints for demonstrating clinical efficacy may be problematic. Measuring significant decreases in the rate of decline of lung function or the frequency of lung infections will require monitoring a large number of patients over a significant period of time. On the favorable side, complex can be aerosolized to reach the desired alveolar region and the levels of AAT needed to be protective may be low. This would argue for the use of a lower dose of complex that would then minimize any inflammatory response associated with the vector.

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