TARGETING THE AGMATINERGIC SYSTEM USING AN AAV-BASED GENE THERAPY FOR THE TREATMENT OF CHRONIC PAIN

Abstract

The complex mechanisms underlying chronic pain and the challenges of current pharmacotherapy leave many chronic pain patients without adequate treatment due to negative physical and social side effects. Thus, there is a critical need to develop new pain management therapies with long-term effectiveness and minimal adverse effects. Using an adeno-associated virus (AAV) gene therapy to treat chronic pain has gained interest in the last twenty years because of several therapeutic advantages. AAV gene therapy allows for selective gene expression directly to sites of interest for chronic pain treatment with the potential for sustained expression following a single injection. In an effort to treat chronic pain using an AAV gene therapy, we have created a viral vector using recombinant adeno-associated virus which encodes the biosynthetic enzyme, human arginine decarboxylase (hADC). Arginine decarboxylase (ADC) is an endogenous enzyme that catalyzes the metabolism of L-arginine into agmatine. Agmatine is an endogenous small molecule that acts as a neurotransmitter and has been previously shown to modulate neuroplastic events by antagonizing the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor. When agmatine is delivered centrally, a reduction in pain behavior following nerve injury is observed. The central hypothesis of this body of work is that overexpression of arginine decarboxylase using an adeno-associated viral vector construct results in long-term reduction of neuropathic pain due to the production of agmatine and subsequent antagonism of the GluN2B NMDA receptor by agmatine. The experiments presented in this dissertation build upon our agmatine-based pharmacotherapy for the treatment of chronic neuropathic pain. Specifically, this work furthers our AAV-based gene therapy by understanding intrathecal AAV kinetics, evaluating how therapeutic efficacy changes with age and with the use of cell-specific promoters, and interpreting associated behavioral implications.