scholarly journals Hemophilia gene therapy: ushering in a new treatment paradigm?

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 226-233
Author(s):  
Lindsey A. George
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Hemophilia A ◽  
Full Potential ◽  
Proof Of Concept ◽  
Aav Vector ◽  
Treatment Paradigm ◽  
Clinical Trial Enrollment ◽  
New Treatment

Abstract After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. With multiple ongoing trials, including licensing studies in hemophilia A and B, many are cautiously optimistic that the first AAV vectors will obtain regulatory approval within approximately 1 year. While supported optimism suggests that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized, a number of outstanding questions have emerged from clinical trial that are in need of answers to harness the full potential of gene therapy for hemophilia patients. This article reviews the use of AAV vector gene addition approaches for hemophilia A and B, focusing specifically on information to review in the process of obtaining informed consent for hemophilia patients prior to clinical trial enrollment or administering a licensed AAV vector.

scholarly journals On Retinal Gene Therapy

2016 ◽  
Vol 236 (1) ◽  
pp. 1-7 ◽  
Author(s):  
M. Dominik Fischer
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Retinal Degeneration ◽  
Basic Science ◽  
Rare Disorders ◽  
Number Of Genes ◽  
The Future ◽  
Treatment Paradigm ◽  
New Treatment ◽  
Retinal Gene Therapy

Mutations in a large number of genes cause retinal degeneration and blindness with no cure currently available. Retinal gene therapy has evolved over the last decades to become a promising new treatment paradigm for these rare disorders. This article reflects on the ideas and concepts arising from basic science towards the translation of retinal gene therapy into the clinical realm. It describes the advances and present thinking on the efficacy of current clinical trials and discusses potential roadblocks and solutions for the future of retinal gene therapy.

Disparities in clinical trials participation in a vertically integrated care delivery system.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 128-128
Author(s):  
Ahmed Megahed ◽  
Gary L Buchschacher ◽  
Ngoc J. Ho ◽  
Reina Haque ◽  
Robert Michael Cooper
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Healthcare System ◽  
Care Delivery ◽  
Trial Participation ◽  
Cancer Type ◽  
Clinical Trial Participation ◽  
Integrated Healthcare ◽  
Clinical Trial Enrollment ◽  
Asian Pacific

128 Background: Sparse data exists on the diversity clinical trial enrollment in community settings. This information is important to ensure equity of care and generalizability of results. Methods: We conducted a retrospective cohort study of members of an integrated healthcare system diagnosed with invasive malignancies (excluding non-melanoma skin cancers) between 2013-2017 to examine demographics of the oncology population compared to those who enrolled in a clinical trial. Logistic regression was used to assess correlates of clinical trial participation, comparing general and screened samples to enrolled sample. Odds ratios were adjusted for gender, geocoded median household income, cancer type, and stage. Results: Of the 84,977 patients with a cancer diagnosis, N = 2606 were screened for clinical trial participation and consented, and of those N = 1372 enrolled. The percent of Latinx (25.8% vs 24.0%; OR 0.9? CI 0.72-1.05) and African American/Black (10.9% vs 11.1%; OR 0.92 CI 0.75-1.11) clinical trial participation mirrored that of the general oncology population, respectively using Non-Hispanic Whites as reference. Asian/Pacific Islander had equal odds of clinical trial enrollment (OR 1.08 CI 0.92-1.27). The enrolled population was younger than the general oncology population. Conclusions: This study suggests that in an integrated healthcare system with equal access to care, the clinical trials population is well representative of its general oncology population.[Table: see text]

AAV9 is considered the most efficient AAV serotype targeting blood-brain barriers. To enhance effective gene therapy for CNS illnesses, testing novel vectors with more efficient crossing capabilities is vital

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Intravenous Injection ◽  
Peripheral Circulation ◽  
Full Potential ◽  
Cns Diseases ◽  
Aav Vector ◽  
Early Clinical Trial ◽  
Blood Brain ◽  
Efficient Gene ◽  
Trial Outcomes

Although gene therapy for CNS diseases shows promise in cell and animal investigations, most human trials have failed to satisfy the requisite requirements. Finding novel techniques to boost the efficacy of gene therapy in treating CNS diseases is still crucial. A growing number of clinical trials have proved the efficacy and safety of using AAV vectors, making AAV vector research a gene therapy hotspot. However, due to the presence of the BBB, many siRNA and DNA with potential therapeutic value are difficult to transport from peripheral circulation to the brain using AAV vectors, limiting the clinical impact of gene therapy drugs in the CNS and posing a major challenge to the field of CNS gene therapy. In early studies, AAV9 was considered the most effective AAV serotype for getting through the blood-brain barrier and transduction to central nervous system cells following intravenous injection. Aavrh10 isolated from rhesus monkeys was equal to, if not superior to, AAV9. AAV-PHP.B, a newly built capsid, exhibits 40-fold greater efficacy than AAV9 in astrocyte and neuron transduction. AAV-PHP.eB, a modified AAV-PHP.B variety, was identified to retain PHP.B's AAV-capacity to transduce astrocytes while enhancing neuronal transduction. While the four serotypes AAV9, AAVrh10, AAV-PHP.B, and AAV-PHP.eB have been validated to penetrate mice's BBB following intravenous injection, the number of AAV vectors that can do so is low. Moreover, the manner in which AAV vectors penetrate the BBB remains unclear. To promote efficient gene therapy for CNS diseases, it is still important to test new vectors with more efficient crossing abilities and understand their crossing processes. In addition to technical challenges, AAV vectors in treating CNS diseases may be limited by cautious attitudes to innovative treatments. Continued advances in AAV vector research, together with early clinical trial outcomes, might help researchers achieve the full potential of AAV-based CNS disease therapies.

Abstract 16910: High-Frequency In-Person Visits During Clinical Trial Enrollment is Associated With Relative Reduction in Event Rates in Heart Failure Patients Followed Longitudinally

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Liana C Brooks ◽  
Rohan R Bhat ◽  
Robyn F Farrell ◽  
Mark W Schoenike ◽  
John A Sbarbaro ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Frequency ◽  
Trial Participation ◽  
Trial Period ◽  
Single Center ◽  
Hospitalization Rates ◽  
Visit Frequency ◽  
Clinical Trial Enrollment ◽  
Event Rates

Introduction: The COVID-19 Pandemic has mandated limiting routine visit frequency for patients with chronic cardiovascular (CV) diseases. In patients with heart failure (HF) followed longitudinally, the period of clinical trial participation provides an opportunity to evaluate the influence of high-frequency per-protocol in-person visits compared to less frequent routine visits during longitudinal clinical care. Hypothesis: Patients enrolled in clinical trials will have a lower CV and HF event rates during periods of trial enrollment than during non-trial periods. Methods: We examined clinical characteristics, CV and HF hospitalization rates, and outcomes in patients with HF receiving longitudinal HF care at a single center. We evaluated hospitalization rates during the 1-year preceding trial enrollment and hospitalization and death rates during enrollment in clinical trials and for up to 1 year following trial completion. Results: Among the 121 patients enrolled in HF clinical trials, 72% were HFrEF (age 62±11, 19% females, BMI 30.4±6.0, LVEF 25±7, NYHA 2.7±0.6, NT-proBNP 2336±2671) and 28% were HFpEF (age 69±9, BMI 32.1±5.5, 29% females, LVEF 60±10, NYHA 2.4±0.5, NT-proBNP 957±997). Average clinical trial exposure was 8±6.6 months. Per-protocol visit frequency was 16±7 per year during clinical trial enrollment. In the one-year pre-trial period, compared to the within-trial period, CV hospitalizations were 0.88/patient-year vs. 0.32/patient-year (p<0.001) and HF hospitalizations were 0.63/patient-year and 0.24/patient-year (p<0.001), with a mortality rate of 0.04/patient-year during trial participation. In the period of up-to 1 year following the end of trial enrollment CV and HF hospitalizations were intermediate at 0.51/patient-year and 0.27/patient-year with an annualized incremental mortality rate of 0.03/patient-year. Conclusion: In HF patients followed longitudinally at a single center, periods of clinical trial enrollment were associated with high visit frequency and lower CV and HF hospitalization rates. These findings highlight the potential benefits of trial enrollment and high-frequency visits for HF patients at a time when routine visit frequency is being carefully considered during the COVID-19 Pandemic.

Increasing underrepresented minority cancer patient enrollment into cancer clinical trials: A systematic review.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18574-e18574
Author(s):  
Rosa Nouvini ◽  
Patricia A. Parker ◽  
Charlotte Malling ◽  
Kendra Godwin ◽  
Rosario Costas-Muñiz
Keyword(s):  
Systematic Review ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Minority Groups ◽  
Relationship Building ◽  
Institutional Research ◽  
Underrepresented Minority ◽  
Randomized Controlled ◽  
Clinical Trial Enrollment ◽  
Recruitment Model

e18574 Background: Minorities continue to be underrepresented in clinical trials despite the National Institute of Health’s Revitalization Act, passed in 1993, mandating the representation of women and underrepresented minority groups in clinical trials. Studies have shown that although Blacks represent 15% and Hispanics 13% of the cancer population, their clinical trial enrollment rates in are disproportionately low at 4-6% and 3-6% respectively. We conducted a systematic review exploring interventions aimed at improving clinical trial enrollment for racial and ethnic minorities. Methods: A systematic search of PubMed, Cochrane CENTRAL, and Ovid PsycINFO was conducted for English-language studies of humans since 1993. Inclusion criteria included peer-reviewed, U.S.-based studies with interventions aimed to recruit underrepresented minority adult cancer patients into cancer clinical trials. We defined underrepresented minority groups as Black, Hispanic/Latino, Asian, American Indian/Alaska Native and Native Hawaiian/other Pacific Islander. Results: A total of 2471 titles and abstracts were identified and 2324 were excluded based on the eligibility criteria. A full text review was conducted of the remaining 147 articles, of which only 9 met criteria for our review. The interventions included patient navigation/coaching (n = 4), a clinical trial educational video (n = 2), institutional research infrastructure changes (n = 1), a relationship building and social marketing recruitment model (n = 1) and cultural competency training for providers (n = 1). Studies were conducted in a variety of practice settings including national cancer institutes and community practices. The quality of evidence was limited by the heterogeneity of study methods, patient representation and bias. Several studies had a homogeneous population of Black patients. Most studies (n = 7) were single arm trials that compared results to either historical controls or those cited in the existing literature; two studies were randomized controlled trials. A statistically significant improvement in accrual was shown in three of the patient navigation interventions, one of the clinical trial educational videos, the institutional research infrastructure change and the relationship building and social marketing recruitment model. The common threads to many of these successful interventions were support through the cancer care continuum, cultural congruency of research staff and culturally catered clinical trial educational materials. Conclusions: This systematic review illustrates several mechanisms by which to increase cancer clinical trial recruitment for cancer patients of underrepresented minority backgrounds in a variety of clinical settings. Randomized controlled trials with representation of multiple races/ethnicities are needed to further explore the benefits of these interventions.

Comparison of attitudes and beliefs about cancer clinical trial enrollment between physicians, research staff, and cancer patients.

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 170-170
Author(s):  
Grace Hillyer ◽  
Melissa Beauchemin ◽  
Dawn L. Hershman ◽  
Moshe A. Kelsen ◽  
Frances L Brogan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Online Survey ◽  
Cancer Clinical Trial ◽  
Cultural Barriers ◽  
Attitudes And Beliefs ◽  
Research Staff ◽  
Hispanic Patients ◽  
Clinical Trial Enrollment

170 Background: Essential to bringing innovative cancer treatments to patients is voluntary participation in clinical trials but fewer than 10% of cancer patients are enrolled onto a trial. We used a domain-oriented framework to assess barriers to cancer clinical trial enrollment (CTE). Methods: Physicians and research staff completed an online survey in 2017; adult cancer patients not currently enrolled in a trial were interviewed in 2018. Perceived structural, provider- and patient-level barriers to CTE were assessed. Differences in perceptions, attitudes and beliefs toward CTE between physicians and staff, patients by ethnicity, and physicians/staff and patients were examined. Results: In total, 120 physician/staff (64.4% response rate) and 150 cancer patient completed surveys. Interacting with the patients’ family was seen as a CTE barrier by nearly one-third of physicians/staff overall, however, staff much more often stated this barrier than did physicians (44.0% vs. 18.2%, p= 0.007). Hispanic patients more often stated they would join a trial, even if standard therapy was an option compared to non-Hispanic patients ( p= 0.004). Overall, patients, more often than physicians/staff, believed that clinical trials are only offered to people whose disease is hopeless (27.3% vs. 8.7%, p < 0.001) and that CTE does not help patients personally (32.9% vs. 1.8%, p < 0.001). More often physicians/staff believed that patients decline CTE due to language or cultural barriers (57.5% vs. 27.3%, p < 0.001), lack of understanding about clinical trials (63.3% vs. 9.1%, p = 0.001), and mistrust of the medical system (69.2% vs. 36.4%, p= 0.043) than was reported by patients. Patients less often reported declining CTE because of concerns about invasive procedures (9.1% vs. 41.7%, p = 0.02), toxicity (18.2% vs. 60.0%, p= 0.006) or reluctance to be randomized/receive a placebo (27.3% vs. 70.8%, p= 0.005). Conclusions: Our findings indicate a wide gap between provider and patient attitudes and beliefs about CTE. Reconciling these differences will require tailored education to dispel misperceptions and strategies to improve the quality of patient-provider communication.

scholarly journals Clinical Trial Information As a Measure of Quality Cancer Care

2010 ◽  
Vol 6 (3) ◽  
pp. 170-171 ◽  
Author(s):  
Wei Chua ◽  
Stephen J. Clarke
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Care ◽  
Treatment Options ◽  
Small Cell ◽  
Small Cell Lung ◽  
Quality Cancer Care ◽  
Improved Outcomes ◽  
New Treatment ◽  
Clinical Trial Information

Participation in clinical trials enables patients to access new treatment options. Evidence shows improved outcomes in participants compared with nonparticipants in non–small-cell, lung, breast, colorectal, and testicular cancers.

scholarly journals Generation of a Unique Cohort of Hemophilia A Dogs Tolerant to Human FVIII for Evaluating the Safety and Efficacy of AAV Delivery of Wild Type and Variant Human FVIII

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2453-2453
Author(s):  
Giang N. Nguyen ◽  
Lauren Wimsey ◽  
Elizabeth Merricks ◽  
Katherine P. Ponder ◽  
Timothy C. Nichols ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Hemophilia A ◽  
Factor Ix ◽  
Common Mutation ◽  
Large Animal ◽  
Efficacy And Safety ◽  
Aav Vector ◽  
Human Factor Ix

Abstract The hemophilia A (HA) dogs have been a valuable model for evaluating the efficacy of novel hemophilia therapeutics. These dogs have a mutation that is analogous to the most common mutation in humans with severe disease, the intron 22 inversion. The advantages of the hemophilia dog model include: (1) it was predictive of the therapeutic adeno-associated viral (AAV) vector dose in human factor IX (hFIX) clinical trials, (2) it is an outbred immunocompetent species, (3) it demonstrates a clinical bleeding phenotype consistent with patients, including hemarthrosis, and (4) it permits long-term investigation of both efficacy and safety. Our previous studies delivering AAV-canine factor VIII (cFVIII) in the HA dogs demonstrated long-term (up to 10 years of follow-up) dose-dependent cFVIII expression without evidence of an immune response to the cFVIII protein. In hemophilia B preclinical studies, the comparable biological characteristics between canine FIX and hFIX allows preclinical results using cFIX to be translated to clinical studies. In contrast, for hemophilia A, our studies of recombinant cFVIII and human FVIII (hFVIII) proteins demonstrate that cFVIII is a more stable protein that has higher biological activity and is secreted better than hFVIII (Sabatino et al. 2009). Thus, expression of cFVIII following AAV delivery does not accurately predict the therapeutic dose of AAV-hFVIII which is relevant for translation to clinical trials. The challenge of administering AAV-hFVIII to the HA dogs is that this expressed xenoprotein (hFVIII) results in inhibitor formation that precludes the ability to measure transgene (hFVIII) expression. We hypothesized that tolerizing HA dogs to hFVIII will (1) permit accurate evaluation of hFVIII expression and thus predict the therapeutic vector dose and (2) allow the evaluation of the potential immune response of AAV8-hFVIII versus a novel hFVIII variant that has increased activity and secretion (Nguyen et al. 2017). In this study we used a neonatal retroviral (RV) delivery approach to tolerize the HA dogs (n=5) to B-domain deleted hFVIII (hFVIII-BDD). HA neonatal male dogs (S28, S29, V06, V26, V27) were treated with the retrovirus (RV-hAAT-hFVIII-BDD-WPRE) (3x10e9 TU/kg) on day 2 of life. The levels of hFVIII expression after RV delivery were 0.3-6% 4 weeks after RV delivery and plateaued after 6 months to 0.8% (S28), 0.3% (S29), 0% (V06), 1.5% (V26) and 1.7% (V27) based on Coatest assay. At 5-6 months of life the dogs (S28, S29, V06) were challenged with hFVIII-BDD (Xyntha; 25IU/kg; I.V.) weekly for 6 consecutive weeks. Samples were collected before and 15 minutes after each protein challenge to demonstrate the successful infusion of the protein. At 4 weeks after the final challenge, no anti-hFVIII IgG1 or IgG2 antibodies were detected consistent with no evidence of an inhibitor. At 4.5 years of age, S28 and S29 had stable expression of 0.5-1% of hFVIII and were rechallenged with hFVIII-BDD (Xyntha; 25IU/kg per week x 6 wks). No anti-hFVIII IgG1 or IgG2 antibodies were detected 4 weeks after the final protein challenge. Thus, these data demonstrate that all of the RV-hAAT-hFVIII-BDD-WPRE treated dogs that have been challenged (n=3) have been tolerant to hFVIII-BDD. Since the goal of this study is to generate a cohort of HA dogs tolerant to hFVIII-BDD to address the efficacy and safety of AAV8-hFVIII-BDD versus a hFVIII-BDD variant, we treated the first dog (S29) 12 weeks after the second series of protein challenges with an optimized AAV vector cassette containing a codon-optimized hFVIII sequence with a modified transthyretin (TTRm) promoter, AAV8-TTRm-hFVIII-BDD (2x10e12 vg/kg). Prior to AAV administration the hFVIII activity was 0.2%. At 8 weeks post AAV administration, the hFVIII activity increased to 3.5%. No anti-hFVIII-BDD IgG1 or IgG2 was detected after AAV-hFVIII administration. These data demonstrate that low levels of sustained hFVIII expression of 0.2-2% up to 4 years post-retroviral delivery were able to induce and maintain tolerance to hFVIII. Overall, these studies demonstrate that the neonatal HA dogs treated with a retrovirus targeting hFVIII expression to the liver are tolerant to hFVIII and provide a unique large animal model to evaluate both efficacy as well as potential immunogenicity of our novel FVIII variants. Disclosures Sabatino: Spark Therapeutics: Patents & Royalties.

Increasing participation in breast cancer research: (INSPIRE-BrC).

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 53-53
Author(s):  
Brandi Robinson ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Primary Outcome Measure ◽  
Test Method ◽  
Trial Participation ◽  
Lower Survival Rate ◽  
Black Patients ◽  
Clinical Trial Enrollment ◽  
The Impact

53 Background: Increasing black patients’ participation in cancer clinical trials is particularly important because of the population’s lower survival rate. Accrual to clinical trials remains low among the general population (1 to 3%), with recruitment of blacks the lowest of all groups at 0.5 to 1.5%. Clinical trials are key to developing new methods to prevent, detect, and treat cancer. INSPIRE-BrC aims to increase trial participation rates among black patients with breast cancer and examine the relationship between the intervention and attitudes/beliefs on the decision to participate. Methods: A sample size of 123 black patients with breast cancer at five MedStar sites will view a 15 minute, culturally tailored video about clinical trials, which targets six cultural and attitudinal barriers to participation. A pre-test/post-test method is used to determine the impact of the video on three variables — likely participation in therapeutic clinical trials; attitudes toward therapeutic clinical trials (assessed based on the 6 barriers); and actual trial enrollment. Expected Findings: We hypothesize that the intervention will increase clinical trial enrollment compared to our 2012 clinical trial enrollment baseline rate of 6% (22/384) for black patients with breast cancer in five MedStar hospitals. The primary outcome measure is the proportion of black patients with breast cancer who agree to participate in a therapeutic clinical trial among those who sign consent to INSPIRE-BrC. Study findings have the potential to increase patient recruitment as a promising tool for rapid dissemination of a theory-driven, evidence-based model to enhance clinical trial accrual among black patients with cancer. [Table: see text]

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