PAGE TITLE
CHEC peptides as therapies for neurological disorders and a noninvasive diagnostic assay for monitoring inflammatory damage
PAGE SUMMARY
Diagnostic Monitor: The Cunningham lab has discovered methods to monitor central and peripheral nervous system neuronal damage resulting from an increase in the inflammatory enzyme secreted phospholipase A2 (sPLA2). These methods can be used to monitor the progress of neurological diseases and neuroinflammatory damage. Phospholipase A2 enzymes have been demonstrated to be involved in the genesis of behavior deficits and inflammation in animal models of multiple sclerosis. While the exact etiology of multiple sclerosis is unknown, autoimmune inflammatory reactions are upregulated. There is no cure for multiple sclerosis or other neurological disorders, only therapies to alleviate symptoms of the disease and to decelerate disease progression. Exploring different modes of neuronal protection may be advantageous in drug design.
Therapeutic: The Cunningham lab has discovered 9-mer and 7-mer CHEC peptides that are novel potential anti-inflammation therapeutics by inhibiting sPLA2. The peptides stimulate protein repair by activating heat shock protein 70 (HSP 70). Elevated levels of sPLA2 enzymes and the resulting biochemical signaling cascade that occurs upon this elevation have been implicated in the pathology of several neurological diseases, including multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, and systemic inflammation. sPLA2 enzymes are attractive therapeutic targets because of their accessibility in circulation, as well as their connection to inflammatory and cell death mechanisms. Protein aggregate diseases, including Alzheimer’s and Parkinson’s, could also be impacted by these peptides.
Modifications of the cell survival and anti-inflammatory peptide CHEC-9 have been synthesized and tested in vivo. The CHEC-9 peptide is a mimetic of DSEP (diffusible survival evasion peptide), a neuro-cyto protective polypeptide that inhibits inflammatory cells. This peptide has been shown to reduce the spinal cord pathology of multiple sclerosis in an animal model. The peptide protected nerve cells after injection into animal models of other neurodegenerative disorders, such as for ALS. The peptide also stimulates protein disaggregation in in vitro, ex vivo, and in vivo models.
One modification of CHEC-9, termed CHEC-7, has two fewer hydrophobic amino acids and may have greater cell uptake and higher therapeutic efficacy than CHEC-9. A single subcutaneous injection of CHEC-7 in a rat model inhibited the acute rise of plasma sPLA2 activity and provided a more prolonged inhibition of sPLA2 activity than that of CHEC-9.
On the diagnostic side, urine samples from several dozen multiple sclerosis patients were analyzed, and these patients had elevated levels of sPLA2 enzymes compared to healthy patients. The sPLA2 level correlated to ongoing disease activity, with the average enzyme activity higher in relapsing patients compared to stable patients. A colorimetric test strip has been developed, whereby the hydrolysis of the phosphatidylcholine substrate of sPLA2 triggers a reaction with colloidal gold, producing a color change in about five minutes. This test strip allows for an easy measurement to determine the occurrence of this inflammatory marker and whether relapse is imminent. Patients with other disorders characterized by inflammatory flare-ups, including asthma, rheumatoid arthritis, Crohn’s disease, psoriasis, and lupus may benefit from this diagnostic assay.
APPLICATIONS
TITLE: Applications
Therapy for neurological and cardiovascular diseases associated with elevated sPLA2 activity
Anti-inflammatory and neuroprotective compound
Monitor sPLA2 activity in patients with neuroinflammatory disorders
Predict inflammatory episodes and recurrences
Inform treatment decisions
ADVANTAGES
TITLE:Advantages
Oral bioavailability and toxicity tested in vivo animal model
CHEC peptides as broad spectrum uncompetitive inhibitors of sPLA2
CHEC peptides promote neuronal cell survival and inhibit inflammation
Noninvasive sensor of inflammation
Simple colorimetric biosensor test strip
Rapid, inexpensive diagnostic test
Strip testing reduces risk of unnecessary therapeutic intervention and expensive MRI evaluations
IP STATUS
Intellectual Property and Development Status
United States Issued Patent 7,528,112
https://patents.google.com/patent/US7528112B2/en
United States Issued Patent 8,106,019
https://patents.google.com/patent/US8106019B2/en
United States Issued Patent 8,716,223
https://patents.google.com/patent/US8716223B2/en
United States Issued Patent 8,785,401
https://patents.google.com/patent/US8785401B2/en
United States Issued Patent 9,452,195
https://patents.google.com/patent/US9452195B2/en
United States pending patent 15/250,015
https://patents.google.com/patent/US20160361379A1/en
United States pending patent 15/366,317
https://patents.google.com/patent/US20170081701A1/en
PUBLICATIONS
References
Cunningham T.J. et al. Anti-inflammatory peptide regulates the supply of heat shock protein 70 monomers: implications for aging and age-related disease. Rejuvenation Research, 2015, 18(2), p. 136-144.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403226/
Chen S. et al. Secreted phospholipase A2 involvement in neurodegeneration: differential testing of prosurvival and anti-inflammatory effects of enzyme inhibition. PLoS One, 2012, 7(6): e39257.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039257
Cunningham T.J. et al. Uncompetitive phospholipase A2 inhibition by CHEC sequences including oral treatment of experimental autoimmune myeloencephalitis. Open Enzyme Inhibition, 2009.
https://www.researchgate.net/publication/237635139_Uncompetitive_Phospholipase_A2_Inhibition_by_CHEC_Sequences_Including_Oral_Treatment_of_Experimental_Autoimmune_Myeloencephalitis
Cunningham, T.J. et al. Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Neuroinflammation, 2006, 3(26).
https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-3-26
Cunningham, T.J. et al. Inhibition of secreted phospholipase A2 by neuron survival and anti-inflammatory peptide CHEC-9. J. Neuroinflammation, 2006, 3(25).
https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-3-25
Cunningham, T.J. et al. Systemic treatment of cerebral cortex lesions in rats with a new secreted phospholipase A2 inhibitor. J. Neurotrauma, 2004, 21, p. 1683-1691.
https://www.researchgate.net/publication/8047152_Systemic_Treatment_of_Cerebral_Cortex_Lesions_in_Rats_with_a_New_Secreted_Phospholipase_A2_Inhibitor
Contact Information:
Robert Mcgrath
Sr. Associate Vice Provost
rbm26@drexel.edu