Enhanced Drug Access to Eye Tissues

说明书(申请人提供)建议创新地使用合成肽来调节上皮细胞-细胞间的相互作用，以加强基于药物或基因的治疗干预。细胞单层是将药物输送到全身选定位置的主要障碍。暂时进入这些隔室将提供另一种治疗衰弱和危及生命的疾病的方法。最近，Nacelle Treateutics，Inc.发现了一小群离子通道形成肽，它们可以瞬时降低各种转化的上皮细胞单层的电阻(屏障完整性的衡量标准)。这一观察结果超出了目标结果，但其治疗潜力立即被认识到。初步实验表明，在短时间内，肽暴露增加了细胞旁通路对小分子(20 KDa)的通透性，但不能增加大分子右旋糖苷的通透性。我们现在建议探索这些多肽作为眼部上皮屏障短效调节剂的潜在应用。长期以来，人们已经认识到，将亲水性或更大分子量的药物滴注到角膜基质和眼内部分是困难的，部分原因是高度抵抗的外上皮层(S)。例如，药物万古霉素是极亲水的，必须通过注射给眼睛。我们推测，NC-1059与这种或其他亲水性抗生素一起使用应该会极大地增强眼科药物的输送。在接下来的一年里，我们将测量在存在和不存在我们最高效价的多肽NC-1059以及几个对照序列的情况下，荧光标记的抗生素在分离的角膜和巩膜结膜中的转运。这些研究的结果将确定眼睛中可以被这种多肽调节的特定靶向组织，以及可以使用这种方法进入的眼睛区域。将对顺序和合并的管理时间表进行评估。将研究不同摩尔比配方的溶液配方，以提高药效和储存期间的稳定性。这些概念验证研究针对的是通过滴注药物而不是目前使用注射的方法来治疗眼睛的急性感染。

DESCRIPTION (provided by applicant) The innovative use of a synthetic peptide to modulate epithelial cell-cell interactions is proposed for the augmentation of drug- or gene-based therapeutic interventions. Cell monolayers are a major obstacle to delivering drugs to selected locations throughout the body. Transient access to these compartments would provide an additional means to treat debilitating and life-threatening disorders. Recently Nacelle Therapeutics, Inc. identified a small group of ion channel-forming peptides that transiently reduces electrical resistance (a measure of barrier integrity) across a variety of transformed epithelial cell monolayers. This observation was outside of the targeted outcome, but its therapeutic potential was immediately recognized. Preliminary experiments indicated that peptide exposure increased the permeability of the paracellular pathway to small (<20 kDa) but not large dextrans for a short period of time. We now propose to explore the potential applications of these peptides as short-acting modulators of epithelial barriers in the eye. It has long been recognized that delivery of instilled hydrophilic or larger molecular weight drugs into the corneal stroma as well as interior portions of the eye is difficult due in part to the highly-resistive outer epithelial layer(s). For example, the drug vancomycin is extremely hydrophilic and must be administered to the eye by injection. We hypothesize that inclusion of NC-1059 with this or other hydrophilic antibiotics should greatly enhance ophthalmic drug delivery. Over the next year, we will measure transport of fluorescently-labeled antibiotics across isolated cornea and sclera-conjuntiva in the presence and absence of our highest potency peptide, NC-1059, as well as several control sequences. The outcomes of these studies will identify specific target tissues in the eye that can be therapeutically modulated by this peptide as well as the areas of the eye that can be accessed using this approach. Both sequential and combined administration schedules will be assessed. Solution formulations with different molar ratio formulations will be investigated for both increased efficacy as well as stability during storage. These proof-of-concept studies are directed toward the treatment of acute infections of the eye through the instillation of drugs in drops rather than the current approach using injections.