Minimally invasive nasal infusion (MINI) approach for CNS delivery of protein therapeutics: A case study with ovalbumin.

One of the primary obstacles in treating central nervous system (CNS) disorders lies in the limited ability of disease-modifying drugs to cross the blood-brain barrier (BBB). Our previously described Minimally Invasive Nasal Depot (MIND) technique has proven successful in delivering various drugs to the brain in rat models via a trans-olfactory mucosal approach. In this study, we introduce a novel Minimally Invasive Nasal Infusion (MINI) delivery approach for administering ovalbumin, a model protein, utilizing a programmable infusion pump (iPRECIO SMP-310R) in a mouse model. This research highlights the significant role of olfactory mucosa in nose-to-brain delivery, with an efficacy of nearly 45% compared to intracerebroventricular (ICV) administration. This demonstrates its potential as an alternative procedure for treating CNS diseases, offering a greater safety profile relative to the highly invasive clinical routes traditionally adopted for CNS drug delivery.

RNA therapies for CNS diseases.

Neurological disorders are a diverse group of conditions that pose an increasing health burden worldwide. There is a general lack of effective therapies due to multiple reasons, of which a key obstacle is the presence of the blood-brain barrier, which limits drug delivery to the central nervous system, and generally restricts the pool of candidate drugs to small, lipophilic molecules. However, in many cases, these are unable to target key pathways in the pathogenesis of neurological disorders. As a group, RNA therapies have shown tremendous promise in treating various conditions because they offer unique opportunities for specific targeting by leveraging Watson-Crick base pairing systems, opening up possibilities to modulate pathological mechanisms that previously could not be addressed by small molecules or antibody-protein interactions. This potential paradigm shift in disease management has been enabled by recent advances in synthesizing, purifying, and delivering RNA. This review explores the use of RNA-based therapies specifically for central nervous system disorders, where we highlight the inherent limitations of RNA therapy and present strategies to augment the effectiveness of RNA therapeutics, including physical, chemical, and biological methods. We then describe translational challenges to the widespread use of RNA therapies and close with a consideration of future prospects in this field.

Nanotechnology-enabled topical delivery of therapeutics in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the paranasal sinuses which represents a significant health burden due to its widespread prevalence and impact on patients' quality of life. As the molecular pathways driving and sustaining inflammation in CRS become better elucidated, the diversity of treatment options is likely to widen significantly. Nanotechnology offers several tools to enhance the effectiveness of topical therapies, which has been limited by factors such as poor drug retention, mucosal permeation and adhesion, removal by epithelial efflux pumps and the inability to effectively penetrate biofilms. In this review, we highlight the successful application of nanomedicine in the field of CRS therapeutics, discuss current limitations and propose opportunities for future work.

Chronic sinusitis is a common inflammatory condition of the sinuses, which affects patients' quality of life and consumes significant healthcare resources. It is primarily treated with corticosteroids, a type of medication that reduces inflammation, as a nasal spray or taken orally. Nasal sprays are preferred, to minimize side effects elsewhere in the body. Recently, another class of drugs ­ 'biologic agents' ­ has been approved for a subtype of chronic sinusitis that causes polyps (grape-like swellings of the sinus lining). However, a lasting cure is elusive, because inflammation frequently returns once these medications are stopped. As our understanding of what causes chronic sinusitis improves, researchers are seeking therapies that more accurately target the cause of inflammation, rather than broadly suppressing all types of inflammation using corticosteroids. The use of nanotechnology allows the design of drugs to overcome various challenges in treating chronic sinusitis, potentially enabling more accurate delivery of drugs into the sinuses, improving drugs' ability to remain on the sinus lining and penetrate it, reducing the amount of drug lost due to the action of outflow pumps and overcoming additional defenses built up by bacteria when they form thick films. Here, we describe how nanomedicine has been used to develop drugs for chronic sinusitis, discuss current limitations and propose opportunities for future work.

Update on allergic fungal rhinosinusitis.

Allergic fungal rhinosinusitis (AFRS) is a unique clinical entity that falls under the broader umbrella of chronic rhinosinusitis with nasal polyps with type 2 inflammation. It is characterized by nasal polyposis, production of characteristic thick eosinophilic mucin, and expansile change of involved sinus cavities. The diagnosis is classically made using the Bent and Kuhn criteria. However, recent studies have indicated the lack of specificity of some major criteria. The need to fulfill all 5 criteria before diagnosing AFRS partially mitigates this but renders the criteria cumbersome to use, and highlights the need to develop more specific criteria. Our understanding of AFRS pathophysiology has advanced significantly and has helped elucidate the lack of histatins contributing to the inability to clear fungal spores, consequently leading to fungi-induced disruption of the epithelial barrier and stimulation of sinonasal epithelial cells. These trigger a cascade of type 2 inflammatory cytokines driven by both the adaptive and innate immune system. Although more research is needed, these findings could hypothetically point to a limited type 3 immune response at the sinus mucosa, resulting in a compensatory overstimulation of type 2 inflammatory processes. Treatment for AFRS remains centered on surgery and topical corticosteroids. Short courses of systemic corticosteroids may be used with caution, and fungal-specific immunotherapy and systemic antifungals are options in recalcitrant disease. Biologics show early promise, as we await data from randomized controlled trials under way. Finally, new insights into AFRS pathology provide opportunities for novel therapeutic strategies.

Grisel's Syndrome in an Adult After Endoscopic Nasopharyngectomy.

BACKGROUND: Grisel's syndrome is rare in adults, and is characterized by nontraumatic atlanto-axial subluxation secondary to infection. Here, we report a case of Grisel's syndrome occurring after endoscopic nasopharyngectomy. METHODS: A 67-year-old man complained of fever and neck pain with reduced lateral rotation after an endoscopic nasopharyngectomy for recurrent nasopharyngeal carcinoma. Flexion and extension X-rays of the cervical spine demonstrated atlanto-axial subluxation, and magnetic resonance imaging showed infective changes with cervical osteomyelitis. A diagnosis of Grisel's syndrome with cervical spine osteomyelitis was made. A later computed tomography (CT) scan demonstrated subluxation of C1 on C2, as well as the occipital-C1 joint. RESULTS: The patient was treated with intravenous antibiotics and offered surgery for spinal stabilization, but declined. He remained well 15 months post-op on a cervical collar with minimal pain and no neurologic deficits. CONCLUSION: A high index of suspicion for Grisel's syndrome is suggested in patients who have neck pain with reduced range of motion postnasopharyngectomy, and imaging is useful in clinching the diagnosis. LEVEL OF EVIDENCE: 4.