Traumatic brain injury (TBI) is a serious global health issue, with 2.2 million new incidents in the US and 52,000 deaths yearly. TBI is a debilitating disease, with the long-term sequelae ranging from functional deficits affecting sensorimotor, learning and memory functions, and varying neurological deficits to coma/vegetative state. Currently there are 5.3 million Americans living with the consequences of TBI; the cost of rehabilitation and loss of productivity has resulted in a financial burden exceeding $60 billion annually, with some estimates as high as $221 billion annually when factoring in loss of quality of life. When added together, TBI incidents outnumber the combined cases of multiple sclerosis, breast cancer, and spinal cord injury (SCI), and demonstrate wider distribution throughout society. Despite its prevalence, thus far there is no effective treatment for this devastating disease. Following TBI, the primary injury causes irreversible and untreatable brain tissue damage. The subsequent secondary injury plays a profound role in the evolution of injury leading to progressive neurodegeneration and cell death. Thus, preventing/treating the additional tissue damage caused by secondary brain insults is the major focus of therapies for TBI. Among secondary injuries following TBI, neuro-inflammation is a prominent event that significantly exacerbates brain tissue damage, causing further functional deficits.
Following TBI, the responses of immune system and central nervous system (CNS) resident glia cells orchestrate a profound inflammatory process. Injury-induced disruption of the blood brain barrier (BBB) causes an increased migration/infiltration of immune cells into the brain. Tissue damage also triggers non-infection immune reactions that are activated by the release of damage-associated molecular pattern molecules (DAMPs) from the injured tissue, which participate in the activation of the innate immune system. CNS-resident microglial cells, whose primary function is patrolling the CNS and removing cell debris, play a major role in the propagation of inflammatory process once activated after injury. Infiltrating immune cells and activated CNS-resident glial cells release a wide spectrum of inflammatory mediators such as prostaglandins, free radicals, complement factors, chemokines, and cytokines, and largely dictate the pathological progression of the injured brain.
To date, abundant studies have shown that targeting neuro-inflammation is a promising strategy for TBI treatment. However, many drugs/agents are incapable of crossing the blood brain barrier (BBB) or have low affinity for CNS cells, and are thus not translatable to the clinic. Because there are currently no FDA-approved agents for TBI, a pressing health care priority is the development of appropriate compounds that can cross the BBB, specifically target CNS cells, and have multiple functions in ameliorating secondary brain injury.
Rationale for Developing SP16 Drug for Treatment of TBI
Low-density lipoprotein receptor–related protein-1 (LRP1) is a ubiquitous membrane receptor functioning as a scavenger and regulatory receptor, inducing anti-inflammatory and pro-survival signals. The binding of protease–inhibitor complexes (such as AAT) to LRP1 inhibits the inflammatory response and induces a pro-survival signal by promoting phosphorylation of protein kinase Akt. Serpin Pharma has synthesized a small peptide (SP16) derived from AAT that functions as an LRP1 agonist. We have recently found that SP16 inhibits NF-kB signaling and the formation of NLRP3 inflammasome in vitro, whereas in vivo, in a mouse acute myocardial infarction model, a single dose of SP16 treatment significantly reduced infarct size and preserved cardiac function.
Sepsis is a common and potentially catastrophic medical emergency. Reflecting Hippocrates, the new Sepsis-3 consensus statement defines it as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” This new definition reflects the importance of host factors and the infecting pathogen, and de-emphasises the prior focus on the systemic inflammatory response syndrome. To die from infection requires the development of organ failure (i.e., sepsis). dexamethasone.
Sepsis in Burn Patients
Sepsis is a major cause of death in intensive care units. In articular, infection is the most common and most serious complication of major burn injuries. In burn patients, sepsis accounts for 50 to 60 percent of deaths, despite the availability of improved antimicrobial therapies. The global sepsis therapeutics market was estimated at $5B in 2010 and was forecast to increase to $17B by 2017.
SP16 offers a new approach for treatment through immune response modulation
- Reduce pro-inflammatory cytokine storm
- Reduce tissue injury cycle through TLR associated DAMP and PAMP regulation
- Decrease immunosuppression
Serpin Pharma has achieved an astounding 60 percent survival rate in a mouse model of lethal endotoxemia (sepsis) when animals were treated with the SP16 peptide drug. Based on this data, Serpin Pharma is working closely with investigators at Johns Hopkins University to develop SP16 for prophylactic treatment of burn victims in intensive care units.
In the US, about 23.6M children and adults have diabetes, and the associated cost is estimated to be $174B (T1&T2DM, ADA). Worldwide, an estimated 284 million people lived with diabetes in 2010 and the number is expected to increase to 438 million in 2030 (World Diabetes Foundation). The combined market size for type I & II diabetes is estimated to be greater than $41B worldwide.
Serpin is currently developing its lead peptide, SP16, for treatment of type II diabetes and was awarded an SBIR grant to test this peptide in mouse models of type I diabetes. Using the FDA- accepted db/db mouse model of type II diabetes, SP16 treatment was shown to improve glycemic control, evidenced by lowered non-fasted blood glucose and HbA1c levels. Similarly, SP16 treatment increased serum C-peptide levels, consistent with improved beta-cell function and/or beta-cell mass.
Rheumatoid arthritis is a chronic, autoimmune and inflammatory disease that affects about one percent of the population of the Western world. RA affects the synovial lining of the joints and commonly results in symmetrical swelling of feet, hands, and knees. There currently are no treatments that can reverse rheumatoid arthritis or the underlying pathology; patients are confined to lifelong monitoring and treatments. The global arthritis therapeutics market was estimated at $20.6B in 2010 and was forecast to increase to $38B by 2018.
Serpin Pharma’s lead peptide, SP16, protects mice against disease in the CAIA (Collagen Antibody Induced Arthritis) model of rheumatoid arthritis. SP16 exhibits significant potential as a disease-modifying anti-rheumatic drug and for this indication.