HSV transfer of Glial cell-derived neurotrophic factor (GDNF) as a treatment of pain

Approximately 9% of the US population suffer from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. This condition precipitates other serious pathologies such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide. Since chronic pain is notoriously difficult to treat using currently available therapeutics, the development of analgesics has represented a major pharmaceutical objective. The origins of pain range from nociceptive (caused by tissue injury or inflammation) to neuropathic, a condition that can have many underlying causes. At initial diagnosis of diabetes, for example, 7.5% of patients already experience pain as a complication of their diabetic neuropathy and by 25 years approximately 45% of diabetic patients suffer from this complication. Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments.

Glial cell-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with pleiotropic effects. It was originally discovered as a survival factor for ventral midbrain dopaminergic neurons but has profound effects on motor neurons, sensory neurons, and other neuronal subpopulations. In adult animals, approximately 60% of DRG neurons express components of the GDNF receptor complex. GDNF receptors are also found in dopaminergic neurons of the substantia nigra, as well as cortex and hippocampus, among other brain regions, as well as on neurons in the spinal cord. As a result of the widespread distribution of GDNF receptors, intrathecal administration of the peptide has many effects, including as recently described an analgesic effect in animal models of neuropathic pain. However, in a human trial involving intraventricular administration of GDNF, severe side effects occurred at relatively low doses, limiting the therapeutic benefit. In a recent publication Hao et al have overcome this limitation by targeting GDNF expression through viral transfer.

Vectors based on recombinant herpes simplex virus (HSV) are uniquely suited to deliver therapeutic transgenes to neurons in the DRG from peripheral subcutaneous inoculation. Replication-incompetent HSV-based vectors are nonpathogenic for neurons in vivo, can be conveniently produced in pure preparations at high titers, and are transported with high efficiency to DRG neurons from peripheral subcutaneous inoculation. In their Molecular Therapy paper Hao et al demonstrate that a GDNF-expressing HSV vector, when administered subcutaneously into the plantar surface of the foot, caused an increase in GDNF release from ipsilateral L4–L6 DRG both in control animals and in animals with spinal nerve ligation. When animals were inoculated two weeks after nerve ligation GDNF-expressing HSV vector produced a sustained and continuous antiallodynic effect lasting 3–4 weeks. This effect could be reestablished by reinoculation at 6 weeks, a time at which antiallodynic was diminished. In contrast, the antiallodynic effect achieved by administration of pharmacologic doses of GDNF peptide disappears within 2–3 days after stopping GDNF treatment.

This promising study indicates that HSV transduction of GDNF represents a simple, long lasting and effective treatment of neurogenic pain that may avoid the unacceptable side effects associated with systemic administration of GDNF. Further clinical studies are eagerly awaited.

Entry date Friday, September 19, 2003

Adapted from Hao et al, Mol Ther. 2003 Sep;8(3):367-75