Ten years after Fire and Melo’s Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2–3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.

The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market

Dry eye disease is a chronic condition of the corneal surface marked by persistent symptoms of irritation or burning that can cause inflammatory damage to the cornea and conjunctiva if untreated. Common risk factors for this syndrome include advancing age, female sex, low humidity environments, systemic medications, and autoimmune disorders. Treatments to relieve symptoms include tear replacement, humidification, improved nutrition, and anti-inflammatory ocular agents. Home healthcare nurses can identify signs and symptoms of dry eye syndrome and initiate strategies that range from warm compresses to physician referrals for more aggressive treatment. Consistent management of this condition improves quality of life and minimizes damage to the ocular surface.

Dry Eye Disease: Prevalence, Assessment, and Management.

Cequa®, a unique and first-in-class preservative free cyclosporine-A (CsA) nanomicellar topical formulation was recently approved by US FDA for treatment of dry eye disease or keratoconjuntivitis sicca (KCS). Being highly hydrophobic, CsA is currently available as an oil based emulsion, which has its own shortcomings. Developing an aqueous and clear formulation of CsA is imperative yet a challenging need in the quest for a safe and better drug product. In this regard, a novel, clear, aqueous nanomicellar solution of CsA was developed which has the potential to deliver therapeutic concentrations of CsA with minimal discomfort to patients. Highly promising pre-clinical results of Cequa® (OTX-101), has led to its advancement to the clinical trials. Phase III clinical trials have demonstrated that OTX-101 is highly effective, safe, and has a rapid onset of action in treating KCS. This review presents a comprehensive insight on formulation development, preclinical and clinical pharmacokinetic results of Cequa®. Additionally, the translational development of Cequa® from the laboratory benchtop to patient bedside has been discussed.

Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease

Any ocular surface disease (OSD), but most commonly, dry-eye disease (DED), can reduce visual quality and quantity and adversely affect refractive measurements before keratorefractive and phacorefractive surgeries. In addition, ocular surgery can exacerbate or induce OSD, leading to worsened vision, increased symptoms, and overall dissatisfaction postoperatively. Although most respondents of the recent annual American Society of Cataract and Refractive Surgery (ASCRS) Clinical Survey recognized the importance of DED on surgical outcomes, many were unaware of the current guidelines and most were not using modern diagnostic tests and advanced treatments. To address these educational gaps, the ASCRS Cornea Clinical Committee developed a new consensus-based practical diagnostic OSD algorithm to aid surgeons in efficiently diagnosing and treating visually significant OSD before any form of refractive surgery is performed. By treating OSD preoperatively, postoperative visual outcomes and patient satisfaction can be significantly improved.

An algorithm for the preoperative diagnosis and treatment of ocular surface disorders.

Dry eye disease (DED) is a multifactorial ocular surface disease that causes symptoms of ocular pain, discomfort, and decreased visual acuity. It significantly affects quality of life of patients. It is more prevalent in the females and is being specifically in the menopausal and postmenopausal age group. This is believed to be due to the changes in balance of sex hormones. Sex hormones - estrogens and androgens - influence production of all components of the tear film including aqueous layer, lipid, and mucin. Various mechanisms such as decrease in hormonal levels, shift in feedback mechanisms, and changes in receptor receptivity interplay to alter the ocular surface homeostasis and subsequently result in DED. Several studies have suggested potential role of hormone replacement therapy in menopause-associated dry eye symptoms. The purpose of this review is to help the non ophthalmic physicians about DED encountered commonly in menopausal age group. It is important for primary care physicians to understand DED due to its high prevalence, often debilitating symptoms and the potentially preventable and treatable nature of the condition.

Dry Eye Syndrome in Menopause and Perimenopausal Age Group.

Dysfunctional tear syndrome (DTS) is a common and complex condition affecting the ocular surface. The health and normal functioning of the ocular surface is dependent on a stable and sufficient tear film. Clinician awareness of conditions affecting the ocular surface has increased in recent years because of expanded research and the publication of diagnosis and treatment guidelines pertaining to disorders resulting in DTS, including the Delphi panel treatment recommendations for DTS (2006), the International Dry Eye Workshop (DEWS) (2007), the Meibomian Gland Dysfunction (MGD) Workshop (2011), and the updated Preferred Practice Pattern guidelines from the American Academy of Ophthalmology pertaining to dry eye and blepharitis (2013). Since the publication of the existing guidelines, new diagnostic techniques and treatment options that provide an opportunity for better management of patients have become available. Clinicians are now able to access a wealth of information that can help them obtain a differential diagnosis and treatment approach for patients presenting with DTS. This review provides a practical and directed approach to the diagnosis and treatment of patients with DTS, emphasizing treatment that is tailored to the specific disease subtype as well as the severity of the condition.

Sheri Rowen

Papers

Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment