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

Objective: 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. Methods: 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. Results: 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. Interpretation: 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. ANN NEUROL 2011Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86983/1/22446_ftp.pd

Pathology Case Study: Left Chest Mass

This soft tissue pathology case, provided by the University of Pittsburgh Department of Pathology, illustrates the process of diagnosing the cause of a patientâs chest and back pain. A chest X-ray and CT scan revealed a chest mass. A biopsy of the mass was performed. Microscopic images of the biopsy are included in the case study along with a gross description and image of the specimen. The official final diagnosis is accompanied by a discussion of the contributing doctorâs findings and a list of references. This is an excellent resource for students in the health sciences to familiarize themselves with the diagnostic process and techniques

A Clinical Trial of Gene Therapy for Chronic Pain

The first human trial of gene therapy for chronic pain, a phase 1 study of a nonreplicating herpes simplex virus (HSV)-based vector engineered to express preproenkephalin in patients with intractable pain from cancer, began enrolling subjects in December 2008. In this article, we describe the rationale underlying this potential approach to treatment of pain, the preclinical animal data in support of this approach, the design of the study, and studies with additional HSV-based vectors that may be used to develop treatment for other types of pain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74369/1/j.1526-4637.2009.00720.x.pd

Immobilized Cobalt Affinity Chromatography Provides a Novel, Efficient Method for Herpes Simplex Virus Type 1 Gene Vector Purification

Herpes simplex virus type 1 (HSV-1) is a promising vector for gene therapy applications, particularly at peripheral nerves, the natural site of virus latency. Many gene vectors require large particle numbers for even early-phase clinical trials, emphasizing the need for high-yield, scalable manufacturing processes that result in virus preparations that are nearly free of cellular DNA and protein contaminants. HSV-1 is an enveloped virus that requires the development of gentle purification methods. Ideally, such methods should avoid centrifugation and may employ selective purification processes that rely on the recognition of a unique envelope surface chemistry. Here we describe a novel method that fulfills these criteria. An immobilized metal affinity chromatography (IMAC) method was developed for the selective purification of vectors engineered to display a high-affinity binding peptide. Feasibility studies involving various transition metal ions (Cu(2+), Zn(2+), Ni(2+), and Co(2+)) showed that cobalt had the most desirable features, which include a low level of interaction with either the normal virus envelope or contaminating DNA and proteins. The introduction of a cobalt-specific recognition element into the virus envelope may provide a suitable target for cobalt-dependent purification. To test this possibility, we engineered a peptide with affinity for immobilized cobalt in frame in the heparan sulfate binding domain of HSV-1 glycoprotein B, which is known to be exposed on the surface of the virion particle and recombined into the viral genome. By optimizing the IMAC loading conditions and reducing cobalt ion leakage, we recovered 78% of the tagged HSV-1 recombinant virus, with a >96% reduction in contaminating proteins and DNA

Chapter 7 Gene Transfer to Muscle and Spinal Cord Using Herpes Simplex Virus-Based Vectors

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GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixedmeal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P = 0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.