Gene Therapy for Pain: A Perspective

Gene Therapy for Pain: A Perspective

Neuropathic pain is a chronic condition that is often refractory to treatment with available therapies and thus an unmet medical need. Is it possible that the neuropathy could have some link to the Herpes Simplex One virus? Not surprisingly, pain—ranging from itching and tingling to severe burning sensations—is a leading feature of PN. Chronic idiopathic polyneuropathy of a primary demyelinating type developed in a man who had had recurrent herpes simplex 2 for 10 years. Subjects receiving a low dose of NP2 reported no substantive effect, while subjects in the middle and high dose cohorts reported clinically meaningful pain relief as measured by patient reported numeric rating scale (NRS) and Short Form McGill Pain Questionnaire (SF-MPQ) for four weeks following injection of NP2. CONCLUSIONS: Progressive outer retinal necrosis is not confined to patients with underlying severe immunodeficiency, such as acquired immune deficiency syndrome. For the first two weeks participants will receive 1 mL of study drug subcutaneously every other day.

In particular, this invention relates to treatment of neuropathy, shingles, dermatitis, and a variety of the Herpes virus, including Herpes Zoster, Herpes Simplex I, and Herpes Simplex 2. The approach of using HSV-mediated gene transfer to treat pain is based on the premise that targeted delivery and expression of genes coding for anti-nociceptive products to DRG neurons can be used to produce analgesic effects by selectively interfering with nociceptive input at the anatomic level corresponding to the regional distribution of the pain. Among the potential viral-based gene transfer vectors, HSV is particularly well-suited for this purpose since the parental wild-type virus from which the replication defective gene transfer vectors are constructed naturally targets DRG neurons from skin infection to establish a life-long persistent (latent) state. The NP2 vector administered to subjects contained the gene for human preproenkephalin. The aim of this case report is to underline that the diagnosis of autonomic autoimmune neuropathy with pure autonomic failure can still be strongly considered in the absence of acetylcholine receptors antibodies and good recovery after treatment with IVIg. Diabetes Reversing By Regenerating Pancreas Seminar In this 45-minute video seminar, Professor Majid Ali, M.D. IL-4 produced by subcutaneous inoculation of S4IL4 suppressed expression of p-p38 but not pERK in the dorsal horn.

In particular, demonstration of hyperalgesia to noxious thermal stimuli and allodynia to cold and mechanical stimuli are used as outcome measures. Sergott et al. Long term treatment for neuropathic pain arising from spinal cord injury (SCI) remains an important health care problem [1⇓–3]. Consider capsaicin cream for people with localised neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments. 2001; Meunier et al. 2005; Yeomans et al. 2006).
Gene Therapy for Pain: A Perspective

We chose to proceed with a clinical trial in patients with intractable pain resulting from terminal cancer because, despite the evidence of safety from preclinical biodistribution and toxicology studies, this was the first clinical trial using HSV to deliver transgenes to patients. shRNA-B and shRNA-C knockdown Nav1.3 protein levels in HEK-Nav1.3 cells. We have constructed a synthetic gene cassette that produces endomorphin peptides, the endogenous agonists for the mu opioid receptor. Often, both large- and small-diameter neurons are affected, resulting in numbness, paresthesia, and burning pain. 2009), and through actions on the mu opioid receptor is likely to have anti-inflammatory effects as well. Transduction of DRG with an HSV vector expressing glutamic acid decarboxylase (GAD) resulted in constitutive release of gamma amino butyric acid from afferent terminals in the dorsal horn and reduced pain-related behaviors in animal models of neuropathic pain resulting from nerve injury or from diabetes (Hao et al. 2005; Chattopadhyay et al.

2011). The treatment is applied as a cream having an active ingredient of approximately 25%, or more, zinc oxide mixed with a suitable excipient such as baby oil or petroleum jelly. HSV is not the only vector that can be used to modify pain-related behaviors. In animal studies, gene transfer achieved by intrathecal injection of non-viral plasmid-based gene transfer vectors, as well as adenovirus, adeno-associated virus (AAV)-, and retroviral-based gene transfer systems have been shown to provide analgesic effects in a wide range of models of pain (Cope and Lariviere 2006), presumably by producing continuous release of peptides with analgesic effects from transduced meningeal cells. Transduction of neurons in the DRG has been demonstrated in animal models following direct injection of an AAV-based vector into DRG (Xu et al. IV Ig (Sandimmune®) 400 mg/Kg over three days rapidly improved significantly, the autonomic failure symptoms by reducing the orthostatic hypotension to the extent that she could stand up supported by compressing stockings; another cure was given two weeks later which dramatically improved the patient’s status as the patient recovered of most of her daily activities, with the support of a daily fludrocortisone 0.1 mg oral therapy. Such toxins accumulate because not enough oxygen and “oxy-detergents” are available to remove them.

NP2 exemplifies a generalizable HSV vector mediated gene transfer platform that can be employed to deliver genes to DRG neurons by intradermal inoculation, an approach that has been termed the nerve targeting drug delivery system (NTDDS). This suggests that the signals involved in pathological nociception arise from the intact neurones. Margolis et al. With the advent of third-generation lentivirus vector technology, in vivo gene therapy approaches have become feasible [40]. Chronic pain is a difficult clinical problem, and the history of drug discovery in this field over the past several decades has not been encouraging (Burgess and Williams 2010; Kissin 2010). Advances in the basic understanding of acute and chronic pain have greatly expanded the range of potential targets for analgesic therapy. But just as with well-established analgesic drugs, like opiates, whose use is often limited by the widespread distribution of receptors that result in side effects from systemic administration, even newly discovered targets that may initially appear to be expressed exclusively in nociceptive pathways (Premkumar and Sikand 2008) are often found to be widely distributed.

Gene transfer, if it proves successful in placebo-controlled studies, is not an approach that is likely to be useful for all forms of chronic pain. For example, gene transfer to DRG would not be applicable to diffuse pain syndromes such as that seen in fibromyalgia, and is unlikely to be useful in central pain syndromes such as occur after thalamic stroke. Double immunostaining of green fluorescent protein (GFP) (green) and NeuN neuronal marker (red) on a representative transverse section of L4 …

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