Gene Therapy for Pain

Gene Therapy for Pain — Why?

Unrelieved chronic pain in the face of debilitating side effects from systemic opioids is one of the most disruptive cancer-related events for patients and their families. Opioids are the only class of drugs effective enough to control severe cancer pain. Pure opioid agonists like morphine have no ceiling effect (i.e. worsening pain can always be suppressed by higher doses) and limitations of their use are based upon the appearance of side-effects. Thus, enhancing the selectivity of the drug response would be of major benefit in patient care. Selectivity of drug action can be achieved in several ways. For some transmitter classes, agents have been developed that interact with subpopulations of receptors such as β1- or β2-adrenergic drugs for the treatments of heart disease or asthma. Although there is evidence suggesting a similar situation in the opioid field, there are no such drugs currently available.

Targeting the "Pain Gate"

An alternative approach is to limit the site of action of a drug to regions that mediate the desired action and not those that are problematic. Spinal opioid targeting is such a strategy focusing drug activity on a site in the nervous system, where it is effective yet causes no side effects, an area sometimes referred to as the "pain gate." Spinal opioids have been widely used to administer opioids, leading to excellent analgesia with limited side-effects. However, analgesia after a single administration lasts only few hours and the requirement for implantation of devices has limited the usefulness of this methodology. Spinal analgesia can be achieved by intrathecal adenovirus expressing prepro-β-endorphin (ppβ-EP), an artificial opioid peptide precursor gene that we constructed for the treatment of pain and reported previously (Beutler, Banck et al. 1995). However, adenovirus vectors elicit a strong immune response that limits the duration of analgesia to one week. Therefore, we searched for alternative gene vectors providing long-term efficacy for the treatment of chronic pain.

Adeno-Associated Virus (AAV) Vectors for Chronic Pain

In 2008, our laboratory published a study demonstrating highly efficient and selective gene transfer into primary sensory neurons and long-term control of neuropathic pain. A special subtype of AAV vector was chosen, self-complementary sc-rAAV8 vectors, which was administered into the lumbar CSF. Transduction was selective for DRG neurons and did not affect other cells of the CNS. At the center of our study was the demonstration of efficacy in a chronic neuropathic pain model, an important functional outcome. Unlike previous reports, the observed efficacy was long-term, lasting for at least 3 mo after a single administration of vectors. The injection technique was atraumatic modeling a lumbar puncture. In the clinic, a lumbar puncture is a common procedure that can be performed safely at the patients bedside. The approach therefore has the potential for clinical translation in the future.

Read more about our work on gene therapy for pain in our original articles (Storek, Harder et al. 2006; Storek, Reinhardt et al. 2008) or reviews (Beutler, Banck et al. 2005; Beutler and Reinhardt 2009).