With coronavirus disease 2019 (COVID-19) emergency solving the unmet medical needs (UMNs) has become even more urgent than before. The COVID-19 pandemic has placed national health systems as well as scientific research communities under enormous pressures with drug repositioning considered the quickest possible transition from bench to bedside for UMNs (Singh et al., 2020). Being conceived before this pandemic occurred, the present Special Issue is far from addressing the pitfalls of COVID-19 management. However its topical interest is absolutely evident. It is well recognised that the larger the disease burdens, the greater the degree to which need is unmet. According to the Article 4 paragraph 2 of Commission Regulation (EC) No. 507/2006 of 29 March 2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 of the European Parliament and of the Council UMN “means a condition for which there exists no satisfactory method of diagnosis, prevention or treatment in the Union or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected”. Consistently, clinical testing and approval of new medicines can undergo through an accelerated authorisation procedure. This topic is focused thanks to the review by C. Scavone and coll. untitled The New Paradigms in Clinical Research: From Early Access Programs to the Novel Therapeutic Approaches for Unmet Medical Needs. Besides this extended review describing the regulatory frame and the more important criticism of new drugs covering UMNs, other 16 papers between review and research papers have been collected. Their apparent high heterogeneity in the subjects and aims reflects the existence of many important UMNs in different medical areas as well as the lack of a real consensus on the definition and interpretation of UMN (Vreman et al., 2019). Consistently, the search on PubMed.gov using keyword “unmet therapeutic needs” retrieves 5,100 results, with a variety of specific therapeutic areas that reflects the complexity of the topic. Actually, the above definition of UMN includes the concept of “satisfactory method” or, in other words “adequate treatment” and “major therapeutic advantage”, also meaning “significant benefit”. This implies: (i) the degree of disease severity or burden, (ii) the lack of effective drugs; (iii) the existence of non-responders among the treated patients; (iv) the poor adherence to the prescribed regimen affecting the extent of concordance or compliance in medicine taking, and therefore conditioning the pharmacotherapy response; (v) the need for safer drugs; (vi) the route of drug administration eventually related to the delivery formulation to improve both the pharmacokinetic and the compliance in medicine taking.
These are the main areas covered by the papers collected in the present Special Issue.
One of the areas where the UMNs are clearly evident is oncology. The burden of cancer and the mortality associated makes clear how all the different challenges cited above have to be faced (Smith et al., 2015). Several exemplary studies can be found in this Issue. For instance, the paper entitled Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting by H. Alshaker and co-authors. approached the study of the oncogenic signalling to explore the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancers underling the importance of the RNA transcriptome microarray analysis.
The Research Snapshot Article by S.S. Sakhnevych et al. Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape further underling the importance of understanding the oncogenic signalling which controls immune escape in order to select correct therapeutic targets and develop new approaches for immunotherapy of cancer.
The personalised medicine emphasises the importance to predict which patients can experience the best benefit and which the worse adverse effects. The herein included paper from A.K. Giri and T. Aittokallio DNMT Inhibitors Increase Methylation in the Cancer Genome approaches this topic identifying 638 novel hypermethylated molecular targetsinfluencing the response to DNA methyltransferase inhibitors.
The synergic effect of different compounds to improve the long-term survival of oncologic patients subjected to conventional chemotherapy is another hot topic. Accordingly, a prototype for a novel antileukemic therapy is described by A. Trachtenberg and colleagues in Synergistic Cytotoxicity of Methyl 4-Hydroxycinnamate and Carnosic Acid to Acute Myeloid Leukemia Cells via Calcium-Dependent Apoptosis Induction.
The topic of dose reduction to limit multiple side effects of chemotherapeutic regimens is critical to solve at least part of the UMNs in oncology. Consistently, paclitaxel, together with others microtubule inhibitors such as nocodazole and vinorelbine dose-response curves were investigated by D.M. Potashnikova and collaborators in the study Non-linear Dose Response of Lymphocyte Cell Lines to Microtubule Inhibitors demonstrating, at the cellular level, how the dose can influence the clinical response in terms of cell cycle arrest and cell death.
Also the topic of the development of new formulations applied to oncology is also reported. The paper Paclitaxel-Loaded Nanosponges Inhibit Growth and Angiogenesis in Melanoma Cell Models by M. Argenziano and coll. assess the problem of how an already existing agent, like paclitaxel,could be expected to increase the positive efficacy/risk ratio through an innovative technological approach based on nanoformulation.
A wide spectrum of nanoformulations is constantly under investigation to address the need of improving the pharmacological and therapeutic properties of drugs (Bamrungsap et al., 2012). Apart the above cited paclitaxel-loaded nanosponges, an example of functionalised gold nanoparticles is also described in this Issue. As highlighted by I.M. Yasinska et al. in Targeting of Basophil and Mast Cell Pro-Allergic Reactivity Using Functionalised Gold Nanoparticles, gold nanoparticles can be used as a platform for non-toxic delivery of signalling inhibitors circumventing the side effects of toxic agents such as calcineurin inhibitors thus furnishing potential new antiallergic drugs based on a disease modifying approach (targeting of allergic effector cells).
The review articles by Ingusci S. and coll. Gene Therapy Tools for Brain Diseases and by P.L. Chazot and coll. Histamine and Delirium: Current Opinion focus the attention on another therapeutic area known to presents a number of UMNs: the area of cognitive disorders and other central nervous system disorders, including neurodegenerative diseases. The specific topic of brain disease is very complex and wide itself and the UMNs in this context are related to the unique biological/pathological mechanism(s) involved that reflects the many facets of diseases left to address (Smith et al., 2019). Therefore, as described by Ingusci S. and coll.gene therapy, represents an attractive option to solve the gap. While an exhaustive exploration of the UMNs for brain disease would require a dedicated special issue, herein the example of the search for new anti-epileptic drugs is reported. The paper Embelin Prevents Seizure and Associated Cognitive Impairments in a Pentylenetetrazole-Induced Kindling Zebrafish Model by U.P. Kundapcan be brought back to a basic research approach to develop a new drug, embelin (produced by Embelia ribes) to obtain a potential candidate against chronic epilepsy-related cognitive dysfunction with an improved efficacy/risk ratio (retarding seizure and improving cognitive impairment) compared to the existing therapies.
A similar approach has been described in this Special Issue also in different therapeutic areas, such as in pathological bone resorptive diseases, osteoporosis, periodontitis, and rheumatoid arthritis, included. This is the example of the novel imidazole derivative KP-A038 described by H.J. Ihn and coll. (Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1). Again, the paper by M. Durante and coll. Effects of PARP-1 Deficiency and Histamine H4 Receptor Inhibition in an Inflammatory Model of Lung Fibrosis in Mice, focusing on lung fibrosis, is based on the new target identification approach, expanding this concept to the possibility of a combination strategy to improve the benefit/risk ratio adding the selective inhibition of the histamine H4 receptor to non-toxic doses of selective PARP-1 inhibitors.
Actually, this idea of the identification of a new potential target to solve the effectiveness pitfalls of the existing therapies finds in the Review Glucocorticoid-Induced Leucine Zipper: A Novel Anti-inflammatory Molecule by O. Bereshchenko a clear and complete description focusing on how also consolidated therapeutic area like inflammation deserves the design of new therapeutic approaches to improve the glucocorticoids benefit/risk ratio.
According to the WHO, cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. Therefore, CVDs represent another important area in which UMNs persist. Two papers approach this specific topic: the one by H. Huang (Rolipram, a PDE4 Inhibitor, Enhances the Inotropic Effect of Rat Heart by Activating SERCA2a) and the one by H. Loi (Metformin Protects the Heart Against Hypertrophic and Apoptotic Remodeling After Myocardial Infarction). The first one used the prototype of phosphodiesterase-4 inhibitors to validate this target for developing agents for the treatment of heart failure. The second one examined the opportunity of a drug repositioning approach to treat of the hypertrophic remodelling after myocardial infarction. An approach, this last one, that could have important clinical benefits reducing the experimental time being based on a well-known commercially available drug like metformin in the specific.
About UMNs, some researches looks at the polychemical medical approach, such as traditional Chinese medicine, as a possible way to fill that gap (Cheng, 2015) like in the paper Epigoitrin, an Alkaloid From Isatis indigotica, Reduces H1N1 Infection in Stress-Induced Susceptible Model in vivo and in vitro by Z. Luo. This approach is validated by the consistency of preparation, evidence-based clinical efficacy, safety and knowledge of the mechanism of action, as reported in the present paper.
In conclusion, the present Special Issue, containing 3 Review articles, 1 Mini Review, 3 Brief Research Reports, 1 Research Snapshot and 9 Original Research papers explores and exemplifies the main challenges in approaching the UMNs including (i) the identification of disease etiopathology and the underlying determinant molecules, (ii) the development of new drugs against novel targets or agents with higher selectivity for existing targets to improve the positive efficacy/risk ratio of the available therapeutic options, (iii) new strategies for drug administration that could offer better clinical outcomes.
