Rare diseases, affecting millions globally, pose a significant healthcare burden despite impacting a small population. While approximately 70% of all rare diseases are are genetic and often begin in childhood, diagnosis remains slow and only 5% have approved treatments. The UN emphasizes improved access to primary care for these patients and their families. Whole-genome sequencing (WGS) and next-generation sequencing (NGS) offer hope for earlier and more accurate diagnoses, potentially leading to preventative measures and targeted therapies. This study explores the therapeutic landscape for rare diseases, analyzing drugs in development and those already approved by the European Medicines Agency (EMA). We differentiate between orphan drugs with market exclusivity and repurposed existing drugs, both crucial for patients. By analyzing market size, segmentation, and publicly available data, this comprehensive study aims to pave the way for improved treatments and a brighter future for rare disease patients.

In recent years, primary familial brain calcification (PFBC), a rare neurological disease characterized by a wide spectrum of cognitive disorders, has been associated to mutations in the sodium (Na)-Phosphate (Pi) co-transporter SLC20A2. However, the functional roles of the Na-Pi co-transporters in the brain remain still largely elusive. Here we show that Slc20a1 (PiT-1) and Slc20a2 (PiT-2) are the most abundant Na-Pi co-transporters expressed in the brain and are involved in the control of hippocampal-dependent learning and memory. We reveal that Slc20a1 and Slc20a2 are differentially distributed in the hippocampus and associated with independent gene clusters, suggesting that they influence cognition by different mechanisms. Accordingly, using a combination of molecular, electrophysiological and behavioral analyses, we show that while PiT-2 favors hippocampal neuronal branching and survival, PiT-1 promotes synaptic plasticity. The latter relies on a likely Otoferlin-dependent regulation of synaptic vesicle trafficking, which impacts the GABAergic system. These results provide the first demonstration that Na-Pi co-transporters play key albeit distinct roles in the hippocampus pertaining to the control of neuronal plasticity and cognition. These findings could provide the foundation for the development of novel effective therapies for PFBC and cognitive disorders.

Genetic obesity such as Prader Willi syndrome (PWS) is a multifaceted condition influenced by various elements, including genetic predisposition, environmental factors, and behavioral components. This meta-analysis explored the reported efficacy of therapeutics in clinical trials for PWS by evaluating clinical endpoints reached in the course of the study and the adverse events observed for each. We looked at GLP1 receptor mediated and non-GLP1 receptor mediated therapies and compared their performance in study arms across time and standard of care. In addition, we estimated the present market shares across different obesity and diabetes assets which have been tested against PWS. In conclusion, the study points to two key readouts. First, existing obesity and diabetes assets are not effective for genetic obesity such as PWS. The unmet needs remain high. Second, the markets for obesity and diabetes are in a stage of expansion. A collaborative approach to therapy development for genetic obesity is required to improve the quality of life for affected individuals.

Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). Our research shows that vagotomy abrogates adult HPC neurogenesis deficits, neuroinflammation and depressive-like behavior, suggesting that vagal afferent pathways are necessary to drive GM-mediated effects on the brain.

COronaVIrus Disease 19 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a group of beta coronaviruses, SARS-CoV-2. The SARS-CoV-2 virus is similar to previous SARS- and MERS-causing strains and has infected nearly six hundred and fifty million people all over the globe, while the death toll has crossed the six million mark (as of December, 2022). In this chapter, we look at how computational modeling approaches of the viral proteins could help us understand the various processes in the viral life cycle inside the host, an understanding of which might provide key insights in mitigating this and future threats. This understanding helps us identify key targets for the purpose of drug discovery and vaccine development.

The study of two prominent viroporins of SARS-CoV-2: Orf3a and (E) protein from a sequential and structural point of view.

Using the bioinformatics and structural modelling approach, we modelled the structure of the envelope (E)-protein of novel SARS-CoV-2, and propose that it plays a critical role in viral infection and pathogenesis.