Minicircle DNA-based Gene Therapy Coupled With Immune Modulation Permits Long-term Expression of ��--Iduronidase in Mice With Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease characterized by mutations to the α--iduronidase (IDUA) gene resulting in inactivation of the IDUA enzyme. The loss of IDUA protein results in the progressive accumulation of glycosaminoglycans within the lysosomes resulting in severe, multi-organ system pathology. Gene replacement strategies have relied on the use of viral or nonviral gene delivery systems. Drawbacks to these include laborious production procedures, poor efficacy due to plasmid-borne gene silencing, and the risk of insertional mutagenesis. This report demonstrates the efficacy of a nonintegrating, minicircle (MC) DNA vector that is resistant to epigenetic gene silencing in vivo. To achieve sustained expression of the immunogenic IDUA protein we investigated the use of a tissue-specific promoter in conjunction with microRNA target sequences. The inclusion of microRNA target sequences resulted in a slight improvement in long-term expression compared to their absence. However, immune modulation by costimulatory blockade was required and permitted for IDUA expression in MPS I mice that resulted in the biochemical correction of pathology in all of the organs analyzed. MC gene delivery combined with costimulatory pathway blockade maximizes safety, efficacy, and sustained gene expression and is a new approach in the treatment of lysosomal storage disease.     

Impact of Targeted Therapy on the Quality of End-of-Life Care for Patients With Non–Small-Cell Lung Cancer: A Population-Based Study in Taiwan

Context

Targeted therapies with epidermal growth factor receptor tyrosine kinase inhibitors have been widely used in the treatment of advanced non–small-cell lung cancer (NSCLC). However, little research has focused on the use of targeted therapies at the end of life (EOL).

Cost-effectiveness of Osimertinib as a Second-line Treatment in Patients With EGFR-mutated Advanced Non–Small Cell Lung Cancer in China

PurposeTo assess the cost-effectiveness of osimertinib used as a second-line treatment after failure of epidermal growth factor receptor tyrosine kinase inhibitor therapy for advanced non–small cell lung cancer (NSCLC) in China.MethodsFrom the perspective of China's health care system, a Markov model was used for estimating the costs and health outcomes of osimertinib and 4 platinum-based chemotherapies, including pemetrexed + platinum (PP), gemcitabine + platinum (GP), docetaxel + platinum (DP), and paclitaxel + platinum (TP). Two scenarios were considered, one in all confirmed patients with T790M-positive disease (scenario 1) and the other in all patients whose disease progressed after epidermal growth factor receptor tyrosine kinase inhibitor therapy, which consisted of patients with T790M-positive or T790M-negative NSCLC (scenario 2). Clinical data for transition probabilities and treatment effects were obtained from published clinical trials. Health care resource utilization and costs were derived from local administrative databases and published literature. Deterministic and probabilistic sensitivity analyses were conducted to assess the uncertainty of the results.FindingsIn the base-case analysis, compared with the 4 platinum-based chemotherapies, osimertinib yielded an additional 0.671 to 0.846 quality-adjusted life-year (QALY), with incremental costs of 15,943 to 20,299 USD in scenario 1, and an additional 0.376 to 0.808 QALY with incremental costs of 9710 to 15,407 USD in scenario 2. In the probabilistic sensitivity analysis, the probabilities that osimertinib would be cost-effective were 57.7% in scenario 1 and 58.4% in scenario 2 if the willingness-to-pay threshold were 30,000 USD/QALY, and probabilities would be more than 75 % in both scenarios if the willingness-to-pay threshold were 50,000 USD/QALY.ImplicationsOsimertinib is likely to be cost-effective when used as a second-line treatment of advanced NSCLC in China based on the latest reimbursement price of osimertinib through National Reimbursement Drug List negotiation.     

Antiplatelet Therapy in the Secondary Prevention of Stroke

The main role of antiplatelet therapy in the management of patients with acute ischaemic stroke is to prevent a recurrent stroke or other serious vascular event, such as myocardial infarction.     

Feasibility of Neoadjuvant Ad‐REIC Gene Therapy in Patients with High‐Risk Localized Prostate Cancer Undergoing Radical Prostatectomy

In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk‐3 gene (Ad‐REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 × 10¹⁰, 1.0 × 10¹¹, and 1.0 × 10¹² viral particles (VP) in 1.0–1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 × 10¹² VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan''s nomogram, were enrolled. They received two ultrasound‐guided intratumoral injections at 2‐week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence‐free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad‐REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199)     

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease

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Dimethyl Sulfoxide–Sodium Bicarbonate Infusion for Palliative Care and Pain Relief in Patients With Metastatic Prostate Cancer

ABSTRACT

Prostate cancer (adenocarcinoma of the prostate) is the most widespread cancer in men. It causes significant suffering and mortality due to metastatic disease. The main therapy for metastatic prostate cancer (MPC) includes androgen manipulation, chemotherapy, and radiotherapy and/or radioisotopes. However, these therapeutic approaches are considered palliative at this stage, and their significant side effects can cause further decline in patients’ quality of life and increase non–cancer-related morbidity/mortality. In this study, the authors have used the infusion of dimethyl sulfoxide–sodium bicarbonate (DMSO-SB) to treat 18 patients with MPC. The 90-day follow-up of the patients having undergone the proposed therapeutic regimen showed significant improvement in clinical symptoms, blood and biochemistry tests, and quality of life. There were no major side effects from the treatment. In searching for new and better methods for palliative treatment and pain relief, this study strongly suggested therapy with DMSO-SB infusions could provide a rational alternative to conventional treatment for patients with MPC.     

Measurement Properties of the Eight-Item Abbreviated Functional Assessment of Cancer Therapy—Breast Symptom Index and Comparison With Its 37-Item Parent Measure

ContextThe Functional Assessment of Cancer Therapy—Breast Symptom Index (FBSI) is an eight-item instrument extracted from the Functional Assessment of Cancer Therapy—Breast (FACT-B). There has been no formal assessment of this eight-item version.ObjectivesThis study aimed to examine the measurement properties of and comparability between the English and the Chinese versions of the FBSI and to compare it with its parent instrument, the FACT-B, in breast cancer patients in Singapore.MethodsThis was an observational study of 271 breast cancer patients. Known-group validity of FBSI scores was assessed using four health indicators. Convergent and divergent validity was examined by correlation coefficients between the FBSI and the FACT-B. Responsiveness was assessed in relation to longitudinal changes in performance status. Test-retest reliability was evaluated by the intraclass correlation coefficient. Multiple regression analyses were performed to compare the scores on the two language versions. Receiver operating characteristic curve analyses were used for comparison between the FBSI and the FACT-B.ResultsFor both language versions, the FBSI demonstrated known-group validity, convergent and divergent validity, and sufficient test-retest reliability (intraclass correlation coefficient = 0.75–0.77). The English version was responsive to changes in performance status. The Chinese version was responsive to decline in performance status, but there was no conclusive evidence about its responsiveness to improvement in performance status. No practical significant difference was found in the outcomes between the two language versions despite minor difference in one item. The FBSI performed comparably with the FACT-B.ConclusionThe English and Chinese versions of the FBSI are valid and reliable and provide comparable FBSI scores. The English version is responsive to change, whereas the responsiveness of the Chinese version warrants further study.     

Can Surface Neuromuscular Electrical Stimulation of the Wrist and Hand Combined With Routine Therapy Facilitate Recovery of Arm Function in Patients With Stroke?

Rosewilliam S, Malhotra S, Roffe C, Jones P, Pandyan AD. Can surface neuromuscular electrical stimulation of the wrist and hand combined with routine therapy facilitate recovery of arm function in patients with stroke?ObjectiveTo investigate whether treatment with surface neuromuscular electrical stimulation to the wrist extensors improves recovery of arm function in severely disabled patients with stroke.DesignSingle blinded randomized controlled trial.SettingAcute stroke unit and stroke rehabilitation wards of a university hospital.ParticipantsPatients with no upper limb function (Action Research Arm Test [ARAT] score 0) (N=90; mean age ± SD, 74±11y; 49% men) were recruited to the study within 6 weeks of stroke. Only 67 participants were alive at the end of the study and data from 66 of these people were analyzed.InterventionsParticipants were randomized to surface neuromuscular electrical stimulation using surface electrical stimulators for 30 minutes, twice in a working day for 6 weeks in addition to standardized upper limb therapy or just standardized upper limb therapy.Main Outcome MeasureThe primary outcome measure was the ARAT score. Assessments were made at baseline and at 6, 12, 24, and 36 weeks after recruitment.ResultsThere were statistically significant improvements in measures of wrist extensor (mean difference 0.5; 95% confidence interval [CI], 0.0–1.0) and grip strength (mean difference 0.9; 95% CI, 0.1–1.7) over the treatment period. Arm function (ARAT score) was not significantly different between the groups over the treatment period at 6 weeks (mean difference 1.9; 95% CI, ?2.9 to 6.8) or over the study period at 36 weeks (mean difference 6.4; 95% CI, ?1.8 to 14.7), and the rate of recovery was not significantly different (mean difference 0.7; 95% CI, ?0.2 to 1.6).ConclusionsIn patients with severe stroke, with no functional arm movement, electrical stimulation of wrist extensors improves muscle strength for wrist extension and grip, and larger studies are required to study its influence on arm function.     

Successful Gene Therapy in the RPGRIP1-deficient Dog: a Large Model of Cone–Rod Dystrophy

For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod–cone dystrophies but not in large models of progressive cone–rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone–rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18–72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22–29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone–rod dystrophy provides great promise for human treatment.