PTP1B is recognized as a key driver of obesity and diabetes by world-leading scientists and clinical-experts in these therapeutic areas. To elaborate, preclinical studies have revealed that deleting the gene coding for PTP1B exclusively in the brain results in a decrease in body weight and fat mass, reduced food intake, increased activity and energy expenditure, increased leptin sensitivity, and improved glucose homeostasis. This sought-after phenotype was observed even when fed a high-fat obesity-inducing diet, corroborating the clinical importance of this elusive target. In contrast. PTP1B gene deletion in peripheral organs such as the liver, skeletal muscle or adipose tissue, which have historically been the target of PTP1B inhibition, does not lead to reductions in body weight or fat mass. These important findings led researchers to conclude that “for effective obesity treatment and optimal therapy for type 2 diabetes, PTP1B inhibitors must be directed to the brain” (Source: Neuronal PTP1B regulates body weight, adiposity and leptin action, Bence et al, Nature Medicine, 2006).
Figure 1. Mice lacking neuronal PTP1B weigh less than their littermates, show improved glucose metabolism and reduced food intake independently of their diet.
Potent suppression of PTP1B in the human brain can be achieved using small interfering RNAs (siRNA). To this aim, BioGene has successfully engineered selective, novel, stable, potent siRNAs (‘Smart-siRNAs’) that exquisitely target PTP1B messenger RNA (mRNA), thwarting PTP1B protein production, thereby reinstating normal insulin and leptin signaling.
To support siRNA delivery, a vector/carrier is required, and BioGene has developed a unique non-viral bioresponsive LNP (bLNP) vector platform, one that possesses a patented intracellular gene-cargo releasing feature. Furthermore, BioGene’s bLNPs encompass another truly groundbreaking feature, where the lipid-component of the bLNPs, destined to target PTP1B, also acts directly to inhibit PTP1B protein on endoplasmic reticulum, providing an additional layer of regulation, beyond our Smart-siRNAs.
Several metabolically stabilized siRNAs from our extensive library that display potent gene & protein silencing hold promise for future clinical applications for diabetes & obesity, and beyond.
Figure 2. Biogene has developed an extensive library or unique smart-siRNAs out of which several cadidates show the ability to reduce the expression level of PTP1B
BioGene’s innovation doesn’t stop there, our Smart siRNA-bLNPs will be delivered directly and non-invasively to the brain through the olfactory pathway, via our patient-friendly nasal spray Sol-Gel platform.
Please see here for more information about our Sol-Gel and bLNP platforms that are poised to revolutionize brain specific gene therapies for diabetes and obesity, and beyond!