The project RAPID is based on a family of small molecules called Pyrtriazoles, able to work actively on SOCE process. SOCE mechanism relates to the cross-talk between intracellular organelles and the plasma membrane, and allows for the refilling of the depleted organelles, through calcium ion-flux. The principal components of SOCE are a Ca2+-sensor on the ER membrane (STIM) and a plasma membrane Ca2+-channel (ORAI).
It has been reported that SOCE hyper-activation leads to calcium overload in pancreatic acinar cells (PACs), representing a key trigger for injury and necrosis in Acute Pancreatitis (AP). Furthermore, genetic defects of STIM and ORAI proteins can lead to genetic disorders to skeletal muscles and platelets. Pathologies associated are mainly four:
• Acute Pancreatitis (AP)
• Stormorken syndrome (STRMK)
• York platelet syndrome (YPS)
• Tubular Aggregate Myopathy (TAM)
While AP affects over 10 million people worldwide, the other three syndromes are extremely rare (estimates of about 1/250.000 for TAM and 1/1.000.000 for Stormorken and York platelet syndromes).
Acute Pancreatitis (AP) is the most common gastroenterology discharge diagnosis in Europe and in the US, leading to tremendous emotional, physical, and financial burden.
Gallstones are the most common cause, together with alcohol abuse, hypertriglyceridemia, genetic causes and drug intake. AP is associated with significant disease burden, emergency room visits, frequent hospitalizations, and patients often undergo endoscopic and surgical procedures and are admitted to intensive care.
Despite the great advances in critical care medicine over the past 20 years, the mortality rate of AP has remained high, between 1.5% and 4.2% and deaths are mainly due to failure of multiple organ systems (respiratory, cardiovascular or renal), exacerbation of pre-existing disorders and pancreatic and extra-pancreatic infections. The main clinical and societal need is that for this disease there is no effective pharmacological treatment. Indeed, the current management of AP is supportive, symptomatic and limited to pain relief, nutritional support and fluid resuscitation. Surgery is useful, but limited to pancreatitis due to gallstones, while antibiotics may help only in those episodes where an infection isdocumented.
Finally, invasive techniques indicated for AP management, such as endoscopic retrograde cholangiopancreatography (ERCP), can themselves trigger further episodes of pancreatitis. Overall, long hospitalizations, high-quality supportive and intensive care, surgical and diagnostic procedures, complications and relapses lead to disproportionately high healthcare costs, and it is estimated that about 2.5 B€ are spent annually in Europe in taking care of patients with AP.
Therefore, AP is a disorder with a high medical need, and the introduction of an effective pharmacological treatment would provide high value to patients as well as be cost-effective for payers as it would (i) prevent relapses or chronicization in those patients at high risk; (ii) reduce mortality rate and disability; (iii) reduce direct hospitalizations costs in intensive care units.
