Gene therapy for pain: Results of a phase I clinical trial

Department of Neurology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
Annals of Neurology (Impact Factor: 11.91). 08/2011; 70(2):207-12. DOI: 10.1002/ana.22446
Source: PubMed

ABSTRACT Preclinical evidence indicates that gene transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)-based vectors can reduce pain-related behavior in animal models of pain. This clinical trial was carried out to assess the safety and explore the potential efficacy of this approach in humans.
We conducted a multicenter, dose-escalation, phase I clinical trial of NP2, a replication-defective HSV-based vector expressing human preproenkephalin (PENK) in subjects with intractable focal pain caused by cancer. NP2 was injected intradermally into the dermatome(s) corresponding to the radicular distribution of pain. The primary outcome was safety. As secondary measures, efficacy of pain relief was assessed using a numeric rating scale (NRS), the Short Form McGill Pain Questionnaire (SF-MPQ), and concurrent opiate usage.
Ten subjects with moderate to severe intractable pain despite treatment with >200mg/day of morphine (or equivalent) were enrolled into the study. Treatment was well tolerated with no study agent-related serious adverse events observed at any point in the study. Subjects receiving the low dose of NP2 reported no substantive change in pain. Subjects in the middle- and high-dose cohorts reported pain relief as assessed by NRS and SF-MPQ.
Treatment of intractable pain with NP2 was well tolerated. There were no placebo controls in this relatively small study, but the dose-responsive analgesic effects suggest that NP2 may be effective in reducing pain and warrants further clinical investigation.

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Available from: Joseph Glorioso, Aug 11, 2015
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    • "These studies were important since the translational perspectives of the rodent results were questioned for several reasons, such as the larger size of dermatomes of humans. The first clinical trial of gene therapy for pain was a safety and dose-escalation Phase I study in ten patients with mild to severe intractable pain due to terminal cancer [60]. The protocol consisted in the administration directly in the pain-reporting area of an HSV-1 replicationdefective vector containing the transgene of the precursor of enkephalin [61]. "
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    ABSTRACT: This chapter provides an overview of the main current applications of gene therapy for chronic pain in what concerns animal studies and putative clinical applications. The value of gene therapy in unravelling neuronal brain circuits involved in pain modulation is also analyzed. After alerting to the huge socioeconomic impact of chronic pain in modern societies and justifying the need to develop new avenues in pain management, we review the most common animal studies using gene therapy, which consisted on deliveries of replication-defective viral vectors at the periphery with the aim to block nociceptive transmission at the spinal cord. Departing from the data of these animal studies, we present the latest results of clinical trials using gene therapy for pain management in cancer patients. The animal studies dealing with gene delivery in pain control centres of the brain are analyzed in what concerns their complexity and interest in unravelling the neurobiological mechanisms of descending pain modulation. The chapter will finish by analysing possible futures of gene therapy for chronic pain management based on the development of vectors which are safer and more specific for the different types of chronic pain.
    In Gene Therapy - Tools and Potential Applications, Edited by Francisco Martin Molina, 02/2013: chapter Gene Therapy for Chronic Pain Management: pages 685-701; InTech., ISBN: 978-953-51-1014-9
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    • "All were monitored for severe adverse events (SAEs), other abnormal functions, and their NRS pain scores were monitored for 4 weeks post-injection (wpi). The first key observation from this Phase-I study was that none of the ten patients experienced a treatment-related SAE (Fink et al., 2011 "
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    ABSTRACT: Chronic pain is a major health concern affecting 80 million Americans at some time in their lives with significant associated morbidity and effects on individual quality of life. Chronic pain can result from a variety of inflammatory and nerve damaging events that include cancer, infectious diseases, autoimmune-related syndromes and surgery. Current pharmacotherapies have not provided an effective long-term solution as they are limited by drug tolerance and potential abuse. These concerns have led to the development and testing of gene therapy approaches to treat chronic pain. The potential efficacy of gene therapy for pain has been reported in numerous pre-clinical studies that demonstrate pain control at the level of the spinal cord. This promise has been recently supported by a Phase-I human trial in which a replication-defective herpes simplex virus (HSV) vector was used to deliver the human pre-proenkephalin (hPPE) gene, encoding the natural opioid peptides met- and leu-enkephalin (ENK), to cancer patients with intractable pain resulting from bone metastases (Fink et al., 2011). The study showed that the therapy was well tolerated and that patients receiving the higher doses of therapeutic vector experienced a substantial reduction in their overall pain scores for up to a month post vector injection. These exciting early clinical results await further patient testing to demonstrate treatment efficacy and will likely pave the way for other gene therapies to treat chronic pain.
    Neurobiology of Disease 06/2012; 48(2):255-70. DOI:10.1016/j.nbd.2012.05.005 · 5.20 Impact Factor
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    • "This problem might be overcome if molecular methods , such as targeted gene knock - down or other gene manipulation methods ( Yeomans et al . 2005 ; Fink , 2011 in press ) , could be used to re - set the electrogenistat within central as well as peri - pheral neurons . As new therapeutic candidates are identified and move toward clinical application , it will be increasingly important for clinical and translational scientists to maintain a dialogue with ion channel biologists . "
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    ABSTRACT: In the six decades that have followed the work of Hodgkin and Huxley, multiple generations of neuroscientists and biophysicists have built upon their pivotal contributions. It is now clear that, in mammals, nine genes encode nine distinct voltage-gated sodium channels with different amino acid sequences and different physiological and pharmacological properties. The different sodium channel isoforms produce a multiplicity of distinct sodium currents with different time-dependent characteristics and voltage dependencies, which interact with each other and with the currents produced by other channels (including calcium and potassium channels) to shape neuronal firing patterns. Expression of these sodium channel isoforms is highly dynamic, both in the normal nervous system, and in the injured nervous system. Recent research has shed light on the roles of sodium channels in human disease, a development that may open up new therapeutic strategies. This article examines the pain-signalling system as an example of a neuronal network where multiple sodium channel isoforms play complementary roles in electrogenesis and a strong link with human disease has been established. Recent research suggests that it may be possible to target specific sodium channel isoforms that drive hyperexcitability in pain-signalling neurons, thereby providing new therapeutic strategies for chronic pain, and providing an illustration of the impact of the Hodgkin-Huxley legacy in the clinical domain.
    The Journal of Physiology 03/2012; 590(Pt 11):2601-12. DOI:10.1113/jphysiol.2012.228460 · 4.54 Impact Factor
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