Product name
UC Davis identified b2AR antagonists promoting wound healing, keratinocyte migration and re-epithelization in vitro, in human skin and in preclinical modelSummary
Beta Adrenergic Receptor (beta AR) Signaling as a novel target for optimizing skin wound healingOrganization name
UC Davis Clinical and Translational Science CenteProfile
Keratinocyte migration is a key component in wound healing - it is required for skin reepithelization and complete wound repair. No matter how well the dermis is repaired, without a durable epithelium, the skin cannot be considered to be "healed". Thus, numerous laboratories have focused their efforts on improving keratinocyte migration and wound epithelialization with the ultimate goal of more rapid wound healing in vivo.
The lab of Prof. Isseroff, Dep. of Dermatology, UC Davis School of Medicine concentrated on the role of one of several classes of beta-adrenergic receptors, the beta 2 adrenergic receptor (b2AR) in this process, expressed primarily on human keratinocytes.
Their work demonstrates that blocking of b2AR pathway using pharmacological antagonists (i.e. "beta-blockers") promotes keratinocyte migration and re-epithelization in vitro, in human skin, in an ex-vivo skin wound model, and in vivo in animal preclinical studies.
Based on their preclinical data, they propose a proof-of-concept clinical study on patients with non-healing venous ulcers to determine the safety and efficacy of a currently available (and FDA-aproved) beta blocker, Timolol, for improving ulcer healing.
Core Technology
The b2 AR is a G-protein coupled receptor. B2AR activation results in signaling through different cellular pathways depending on the cell type. Activation of b2AR on keratinocytes affects several cAMP-dependent and -independent pathways that modulate the process of migration. Polymorphisms in b2AR may be also important in modifying the pharmacologic response to bAR-active drugs.
Their previous work demonstrated that activation b2AR on keratinocytes using a receptor agonist (i.e. isoproterenol, approved for use in bronchospasm, cardiac arrest or heart block) significantly inhibits their migration, and affects the rate of wound healing in vitro and in vivo. Catecholamines, such as epinephrine and norepinephrine, are endogenously generated agonists, and these are also generated by the wound epithelium. Therefore it is possible that one contributing pathogenic mechanism contributing to non-healing skin wounds is the chronic activation of b2AR by endogenously generated catecholamines.
Proposed Clinical trial
They propose a proof-of-concept clinical trial using an FDA approved and clinically available topical beta blocker (timolol) for the enhancement of wound healing. The synopsis of this protocol is available on request. It has already been approved by the local VA Northern California Health Systems) IRB. Patients would be recruited from the VA Wound Healing Clinic, of which Dr. Isseroff is the director.
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Description File
Isseroff_BAR_clintrial_708.pdf
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