Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

BACKGROUND: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODS: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTS: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONS: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).

Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID.

BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis. RESULTS: An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient's local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient's local healthcare provider. CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.

FDXR is a biomarker of radiation exposure in vivo.

Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure. Here, FDXR transcriptional changes in blood were investigated in humans undergoing a range of external radiation exposure procedures covering several orders of magnitude (cardiac fluoroscopy, diagnostic computed tomography (CT)) and treatments (total body and local radiotherapy). Moreover, a method was developed to assess the dose to the blood using physical exposure parameters. FDXR expression was significantly up-regulated 24 hr after radiotherapy in most patients and continuously during the fractionated treatment. Significance was reached even after diagnostic CT 2 hours post-exposure. We further showed that no significant differences in expression were found between ex vivo and in vivo samples from the same patients. Moreover, potential confounding factors such as gender, infection status and anti-oxidants only affect moderately FDXR transcription. Finally, we provided a first in vivo dose-response showing dose-dependency even for very low doses or partial body exposure showing good correlation between physically and biologically assessed doses. In conclusion, we report the remarkable responsiveness of FDXR to ionising radiation at the transcriptional level which, when measured in the right time window, provides accurate in vivo dose estimates.

Spontaneous haemothorax from an extramedullary haematopoietic mass.

We report the presentation of a 43-year-old female with an unusual acute complication from an inherited blood dyscrasia. After a provisional working diagnosis of pulmonary embolus, the patient was finally diagnosed with spontaneous haemorrhage from extramedullary haematopoietic foci within the thorax.

A psychological comparison of temporomandibular disorder and chronic daily headache: are there targets for therapeutic interventions?

OBJECTIVE: Temporomandibular disorder (TMD) and chronic daily headache (CDH) are chronic problems affecting the head and face. The aim of this study was to compare TMD and CDH, in terms of cognitive factors, including illness perceptions and coping strategies. STUDY DESIGN: A total of 102 patients, 18 to 70 years of age, classified into 2 groups, TMD or CDH, were recruited in this study from a variety of centres in London. On initial consultation patients underwent clinical examination and were asked to complete 8 questionnaires and checklists evaluating mental and psychological state. Six months later, identical questionnaires were posted to all patients; response rate was 76% and 65% for the TMD and CDH patients, respectively. The data were then analyzed to assess different targets for therapeutic interventions. RESULTS: At first observation, TMD patients were found to have more clinical signs: localized increased jaw sounds, limited mouth opening, arthralgia, and myalgia during palpation, however, the duration of pain was higher in the CDH group. Significant differences (P < .01) in terms of psychological distress, were identified between the 2 groups. The CDH group scored higher in 3/3 bands of the Toronto Alexithymia Scale, indicating difficulty expressing emotion; the consequence band of the Illness Perceptions Questionnaire, indicating they were less likely to expect a cure; and were more likely to catastrophize as shown by the Coping Strategies Questionnaire. The 2/4 bands of the McGill Pain Questionnaire showed that CDH group had more severe pain and more depression as measured by the Hospital Anxiety and Depression Scale. TMD patients scored higher in the control band of the Coping Strategies Questionnaire indicating greater control over pain. However, at 6-month follow-up, the only significant difference (P < .01) was in the physiological band of the Illness Perception Questionnaire, the CDH group scored higher. However, this is probably of limited clinical significance. There were no significant differences except in the depression part of the Hospital Anxiety and Depression Scale, the headache group scored higher. Temporomandibular disorder was reported to be less painful, more controllable, and possibly less responsive to reassurance. CONCLUSION: This study suggests that differences in cognitive findings between the 2 groups of patients are not sustained over time. Initially, the headache patients catastrophized, were more distressed, and more depressed. However, these differences disappeared at follow-up. Significant correlations between perceived performance ("timeline" IPQ); disability and anxious mood; perceived consequence with disability and depressed mood; and catastrophizing (CSG) with pain, disability, and anxious mood present possible targets for therapeutic intervention.