Gene therapy for pain: Results of 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: 9.98). 08/2011; 70(2):207-12. DOI: 10.1002/ana.22446
Source: PubMed


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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    • "A similarly constructed virus has been used in several rodent10–15,25–27 and a non-humane primate28 pain model. A feasibility study in humans using a similar viral vector has recently been published29. Fink et al. found a dose-response curve with analgesic effects lasting at least 28 days with the highest dose investigated after a single administration of the preproenekphalin encoding HSV-based vector in patients that were on high doses of chronic opioids. "
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    ABSTRACT: The aim of this study was to test the efficacy of a single direct injection of viral vector encoding for encephalin to induce a widespread expression of the transgene and potential analgesic effect in trigeminal behavioral pain models in mice. After direct injection of HSV-1 based vectors encoding for human preproenkephalin (SHPE) or the lacZ reporter gene (SHZ.1, control virus) into the trigeminal ganglia in mice, we performed an orofacial formalin test and assessed the cumulative nociceptive behavior at different time points after injection of the viral vectors. We observed an analgesic effect on nociceptive behavior that lasted up to 8 weeks after a single injection of SHPE into the trigeminal ganglia. Control virus injected animals showed nociceptive behavior similar to naïve mice. The analgesic effect of SHPE injection was reversed/attenuated by subcutaneous naloxone injections, a μ-opioid receptor antagonist. SHPE injected mice also showed normalization in withdrawal latencies upon thermal noxious stimulation of inflamed ears after subdermal complete Freund’s adjuvans injection indicating widespread expression of the transgene. Quantitative immunohistochemistry of trigeminal ganglia showed expression of human preproenkephalin after SHPE injection. Direct injection of viral vectors proved to be useful for exploring the distinct pathophysiology of the trigeminal system and could also be an interesting addition to the pain therapists’ armamentarium.
    Full-text · Article · Feb 2014 · Gene therapy
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    • "(i) Gene therapy: Improved understanding of signalling pathways underlying pain generation and transmission, and significant advances in the viral vector designs have led to the development of gene based approach to modulate nociception72. Fink et al73 conducted a phase I clinical trial of NP2, a replication defective herpes simplex virus (HSV) based vector expressing human preproenkephalin (PENK) in cancer pain subjects. The intervention was well tolerated by the subjects. "
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    ABSTRACT: Breast cancer is one of the most prevalent cancers amongst women in the world. Unfortunately, even after adequate treatment, some patients experience severe pain either due to disease progression or due to treatment related side effects. The persistent pain causes a negative physical and psychosocial impact on patients' lives. Current rational pain management is patient-centred and requires a thorough psychological assessment. Usually adequate analgesia is achieved by adopting the WHO's three step analgesic ladder. As the disease progresses, the pain experienced by the patient also increases. This necessitates the administration of opioids and adjuvant analgesics to the breast cancer patients experiencing severe pain. However, opioid use is associated with intolerable side effects like constipation, nausea, vomiting, fear of dependence, and tolerance. Concomitant medications are required to combat these unacceptable side effects. Adjuvant analgesics need to be added to provide adequate and satisfactory analgesia. These factors worsen the psychological state of patients and deteriorate their quality of life. Hence, there is a need to develop therapeutic modalities to provide adequate analgesia with minimum side effects. This review article focuses on the current treatments available for cancer pain management, their limitations, and novel targets and non-pharmacological measures under investigation which have the potential to produce a radical change in pain management measures for the breast cancer patients.
    Full-text · Article · Feb 2014 · The Indian Journal of Medical Research
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    • "In a ten-person, open-label, dose-escalation trial, NP2, an ENK-expressing HSV vector, demonstrated a positive safety profile with no serious adverse events in patients with severe focal pain due to cancer. Analysis of daily numeric pain scores over the course of the study (28 days) suggested a dose-related analgesic response to the drug.58 "
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    ABSTRACT: Chronic pain represents a major medical burden not only in terms of suffering but also in terms of economic costs. Traditional medical approaches have so far proven insufficient in treating chronic pain and new approaches are necessary. Gene therapy with herpes simplex virus (HSV)-based vectors offers the ability to directly target specific regions of the neuraxis involved in pain transmission including the primary afferent nociceptor. This opens up new targets to interact with that are either not available to traditional systemic drugs or cannot be adequately acted upon without substantial adverse off-target effects. Having access to the entire neuron, which HSV-based vector gene therapy enables, expands treatment options beyond merely treating symptoms and allows for altering the basic biology of the nerve. In this paper, we discuss several HSV-based gene therapy vectors that our group and others have used to target specific neuronal functions involved in the processing of nociception in order to develop new therapies for the treatment of chronic pain.
    Full-text · Article · Jan 2014 · Journal of Pain Research
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