Gene Therapy for Chronic Pain: How to Manipulate and Unravel Pain Control Circuits from the Brain? - Gene Delivery and Therapy for Neurological Disorders - page 322

1 Introduction

Chronic pain has a huge impact on the quality of life. The deleterious
effects of chronic pain in human well-being and the huge economic
burden of its treatment demand the development of new therapeutic
approaches. Since the available approaches for chronic pain treatment
remained considerably unchanged during the last decades, gene
therapy emerged as a putatively new fi eld. At the basic science,
pioneer studies on gene therapy consisted of overexpression of opi-
oid peptides at the spinal cord to block the transmission of painful
information to the brain [ 1 ]. These studies explored the natural
affi nity of herpes simplex virus type 1 (HSV-1) to the neuron and
its ability for retrograde transport and consisted of application of
replication-defective forms of the vector at the periphery, in order
to transduce neurons at the dorsal root ganglia. Subsequent
delivery of the opioid peptides at the spinal cord induced analgesia
in several pain models, including rodents and primates. Besides
allowing a more sustained analgesic effect than pharmacological
approaches, HSV-1-based deliveries of opioids have the additional
advantages of preventing tolerance after repeated administrations
of the vector along with the absence of other side effects of classical
opioids [ 2 ]. It was also shown that opioid-based gene therapy can
be very powerful in inducing analgesia if combined with adminis-
tration of very low doses of classical opioids [ 2 ]. Besides opioid
peptides, other transgenes were included in the constructs,
namely, to increase the levels of inhibitory neurotransmitters like
ʳ -aminobutyric acid (GABA), in this case by overexpressing its

synthesizing enzyme, glutamate decarboxylase (GAD) [ 3 ].
The translational perspectives of the detailed studies summarized
in the former paragraph were extremely favorable to implement clini-
cal trials for gene therapy for chronic pain. Important contributions
are currently being provided by phase 3 clinical trials in cancer patients
[ 4 ]. It was shown that patients suffering from severe pain that could
not be managed by classical methods show pain relief after receiving
a peripheral administration of HSV-1 vector containing transgenes of
opioid peptide precursors. Based on these promising results, it has
been proposed that gene therapy could also be useful to other chronic
pain situations, namely, neuropathic pain.
By allowing a sustained and direct manipulation of neurons,
gene transfer provides important knowledge about the role of the
targeted neuronal circuits in pain control. It should be recalled that
there are multiple areas in the brain devoted to inhibit or enhance
pain transmission at the spinal cord. These areas respond to the
arrival of painful information by balancing inhibition and facilita-
tion. In acute pain conditions, inhibition prevails over facilitation.
Chronic pain is thought to derive from enhancement of descending
pain facilitation which is not compensated by increased inhibition.
We have used gene therapy to block pain control centers involved in