Different, well-designed clinical trials have demonstrated the effectiveness of rhDNase I in CF patients. However, the response shows a large interindividual variability; about 50% of CF patients do not benefit from rhDNase I therapy [109]. It has recently been discovered that globular actin may be involved in the failure of rhDNase I in these nonresponders [111]. Therefore, clinical trials are required to elucidate whether actin-resistant variants of human DNases can overcome the inhibition of actin in CF patients who do not respond to rhDNase I.

Small trials and case reports have demonstrated the clinical efficacy of rhDNase I in certain non-CF respiratory diseases and SLE [124,146]. However, these observations have to be confirmed further by detailed, long-term studies. Moreover, the promising hyperactive and actin-resistant variants of human DNases also await clinical investigations in these diseases. Treatment of SLE with DNase will probably require an enduring or prolonged presence of DNase in the serum. This can be achieved via a controlled release of DNase or by introducing in these patients, via gene therapy, a gene encoding DNase.

The recent discovery of the involvement of DNases in apoptosis and cancer has focused the spotlight on these enzymes even more [169]. More anticancer agents based on DNases (especially CAD) or on agents that influence these enzymes will probably emerge in the near future.

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