DELIVERY OF THERAPEUTIC siRNA TO THE LUNG

Just like eyes and skin, lung epithelium and macrophages are anatomically accessible to therapeutic agents through inhalation. Local delivery of siRNA into the lung allows for noninvasive access and avoids interactions with serum proteins that degrade siRNA after i.v. administration,5 from which the delivery of siRNA could be more efficient. In fact, many studies have been conducted over the past few years involving the delivery of siRNAs to the lungs for the treatment of various lung diseases. Delivery of siRNA to the lung may expedite translation of siRNA technology to clinics. On the other hand, because of the prevalence and lethality of various respiratory disorders, the lung is emerging as an attractive target organ for siRNA-mediated cures. According to the World Health Organization, lung cancer is the top eight cause of death worldwide, tuberculosis number 7, chronic obstructive pulmonary disease (COPD) number 4, and lower respiratory infections number 3.8 Thus, the clinical utility of siRNA as inhaled therapeutics is under intensive investigation. Furthermore, pulmonary administration also brings higher local concentration, reduced systemic exposure, and lower risk of enzymatic degradation compared to other administration routes such as oral and injection.9 The lung also offers other advantages over systemic administration such as the large alveolar surface area with high vascularization and the thin air-blood barrier, which are beneficial factors for absorption. Obviously, all of these are beneficial for the treatment of lung-confined diseases. The completion of phase Ilb clinical trial of ALN-RSV01 (details shown in Table 3.1) has demonstrated the feasibility of this administration route.

TABLE 3.1

Examples of siRNA-Based Therapeutics in Clinical Trials for Lung Diseases

Product Name

Delivery Agent/ Route of Administration

Indication

Sponsor

Latest Development Status

ALN-RSV01

Naked siRNA/ intranasal

RSV infection

Alnylam

pharmaceuticals

IIb (completed)

Excellairâ„¢

Unknown/inhalation

Asthma

Zabecor

pharmaceuticals

II

 
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