PhaseBio Wins $2.8M SBIR Grant to Advance Lead Candidate

Adaptive immunity is the ability of specific lymphocytes to differentiate between self and non-self (foreign) antigens and defend the body by selectively destroying non-self-peptides. This concept is possibly the most crucial factor in several immunological medical domains and is increasingly being explored across cancer immunotherapy, vaccine design, pathogen identification, and autoimmune disorders (including allergies). A growing body of literature elucidates the importance of peptides, short amino acid chains linked via peptide bonds, in providing the adaptive immune system with the information required to effectively distinguish between self and non-self particles. This has resulted in the proposal of the ‘immune self’ concept, which postulates that self-similarity is a fundamental determinant of immune recognition. First introduced by Frank MacFarlane Burnet in 1949, the immune self-concept and its sister, the self-nonself theory, have substantially evolved over the decades. Initially driven by observations from Medawar’s early transplantation experiments, Nils K. Jerne (1974; eigen-behavior theory), Polly Matzinger (1994; danger theory), and most recently, evidence from research conducted independently by Waldmann, Mitchison, and Janeway has refined the immune self-concept from ‘all body elements are self, and foreign elements are non-self’ to the most recent ‘infectious non-self (foreign and usually harmful) versus noninfectious self (safe) elements.’

Some bacterial species produce antimicrobial peptides known as bacteriocins that have been used in the food industry as preservatives. For example, nisin, which is produced by Lactococcus lactis, has broad-spectrum bactericidal activity and has been used as a food preservative throughout the world. Nisin is effective in controlling Gram-positive bacteria such as Clostridioides difficile. In combination with other compounds like ethylene diamine tetra-acetic acid and cinnamaldehyde, nisin has been effective in controlling enterotoxigenic Gram-negative bacteria such as Escherichia coli. Previous studies have used chicken and mouse models to demonstrate the in vivo efficacy of nisin on the microbiome, whereas nisin efficacy has been proven in ex vivo experiments on the human microbiome. To date, no studies have assessed the in vivo effects of nisin in large mammals.

It has been noted in around 20 percent of the world population suffers from some form of pain or the other. In many individuals, pain may be relieved initially with pain medications, but soon tolerance develops, and there is a decrease in the efficacy of pain relievers. One of the main symptoms of IBS seen commonly in many sufferers is chronic abdominal pain. Professor Lewis said, "All pains are complex, but gut pain is particularly challenging to treat and affects around 20 percent of the world's population. Current drugs are failing to produce effective pain relief in many patients before side effects limit the dose that can be administered." Professor Brierley echoed this statement saying, "Internal organs have a complex network of sensory nerves that have a wide array of voltage-gated ion channels and receptors to detect stimuli... The hypersensitivity of these nerves in disease often contributes to the development of pain."

These peptides, like the parent compound AC253, acted as antagonists at the AMY receptor. They were also resistant to protein breakdown, and crossed the blood-brain barrier easily when injected into the abdominal cavity, to localize in the hippocampus, which is crucial in memory. These peptides protected the brain against beta-amyloid injury, and normalized the AD-associated impairment of the memory-associated long-term potentiation of nerve impulses in the hippocampus. They improved memory testing results, and reduced the level of inflammation in the brain. These effects appear to be mediated via the blockade of AMY receptors. For instance, inhibition of microglial AMY receptors reduce the activation of the inflammasome NLRP3. This reduces the secretion of inflammatory chemicals in the surrounding brain tissue, which offers another mechanism for lower amyloid production. In addition, these peptides increase the rate of outflow of amyloid beta from the brain, which also contributes to a lower level of amyloid after treatment. These marked changes all occurred within a relatively short span of treatment. A very important additional finding was that treatment with these peptides brought about improvement in mice which were showing signs of well-established AD in the brain as well as in their behavior. This is unique in that most therapies fail to affect the progress of AD once it has begun to manifest clinically. Peptides also have fewer off-target effects. Small molecules are easy to administer, inexpensive to make and cross the blood-brain barrier more rapidly. For this reason, the team resorted to computational tools and artificial intelligence to come up with a new small molecular drug based on these peptides. This can be taken orally, and is similar in size and structure to the medications used for medical conditions like high blood pressure. An optimized version is being developed to enable human trials to be conducted. The work so far has taken about two decades, building step upon painstaking step to come up with the right solution. However, says Jhamandas, “Occasionally you come across a discovery that has the potential to change the game in a very fundamental way, like hitting a home run, and I'm very excited that we are really on to something here.” Short amylin receptor antagonist peptides improve memory deficits in Alzheimer’s disease mouse model. Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang & Jack Jhamandas. Scientific Reports, volume 9, Article number: 10942 (2019). https://doi.org/10.1038/s41598-019-47255-9. https://www.nature.com/articles/s41598-019-47255-9

The endogenous opioids and their receptors are widely distributed throughout the central and peripheral nervous systems, particularly the parts of these systems that regulate pain, emotion, reward, stress responses, motivation, drug addiction, and autonomic control. The differential expression and location of the various receptor subtypes across different neurons account for the wide range of opioid-related behaviors. The activation of µ-opioid receptors is mainly known for playing a role in pain relief. Still, research has also indicated it may be involved in behaviors related to survival, such as appetite and reproduction. The activity of µ-opioid receptors is also known to play a critical role in responses to social stimuli by modulating responses to social rejection or social acceptance, for example. Activation of the δ-opioid receptors and κ-opioid receptors is also known to be involved in pain modulation. Also, studies have shown that NOP activation is involved in pain mechanisms and several behaviors related to psychological stress. Alterations in the endogenous opioid system are suspected to be involved in Parkinson's disease, seizures, neuroprotective mechanisms, and depression.