scholarly journals Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies

Medicina ◽  
2021 ◽  
Vol 57 (1) ◽  
pp. 64
Author(s):  
Alessandro Abbouda ◽  
Filippo Avogaro ◽  
Mariya Moosajee ◽  
Enzo Maria Vingolo
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Phase I ◽  
Late Phase ◽  
Cell Types ◽  
Operative Management ◽  
Therapeutic Window ◽  
Experimental Therapies

Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (−6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (−1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had −17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (−14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies.

scholarly journals Etranacogene dezaparvovec for hemophilia B gene therapy

2021 ◽  
Vol 2 ◽  
pp. 263300402110588
Author(s):  
Courtney D. Thornburg
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Continuous Production ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Plain Language ◽  
Long Term Follow Up

The treatment landscape for hemophilia has been rapidly changing with introduction of novel therapies. Gene therapy for hemophilia is a promising therapeutic option for sustained endogenous factor production to mitigate the need for prophylactic treatment to prevent spontaneous and traumatic bleeding. Etranacogene dezaparvovec is an investigational factor IX (FIX) gene transfer product that utilizes the adeno-associated virus (AAV) 5 vector with a liver-specific promoter and a hyperactive FIX transgene. Here, the development of etranacogene dezaparvovec and available efficacy and safety data from clinical trials are reviewed. Overall, etranacogene dezaparvovec provides sustained FIX expression for more than 2 years and allows for a bleed and infusion-free life in the majority of patients. Safety, efficacy, and quality-of-life data will inform shared decision-making for patients who are considering gene therapy. Long-term follow-up regarding duration of expression and safety are crucial. Plain Language Summary Factor IX Padua gene therapy to boost clotting factor and prevent bleeding for people living with hemophilia B People living with hemophilia have low or missing clotting factor, which can lead to bleeding that is unexpected or caused by a traumatic event (such as a sports injury or surgery). There are two main types of hemophilia: clotting factor (F)VIII deficiency (known as hemophilia A) and FIX deficiency (known as hemophilia B). People living with the severe or moderately severe forms of hemophilia (clotting factor levels below 3% of normal) need regular treatment, typically by infusions into the vein, to stop or prevent bleeding and damage to their joints. Gene therapy is currently being investigated as a new treatment option that introduces a working copy of the clotting factor gene to the liver. Following treatment, clotting factor is produced by the liver. Etranacogene dezaparvovec [Et-ra-na-co-gene dez-a-par-vo-vec] is a form of gene therapy for people living with hemophilia B. This form of gene therapy includes a modified form of FIX (FIX Padua) which produces high levels of FIX activity compared with normal FIX. It is being tested to see whether individuals will have low rates of bleeding and not need to treat themselves with clotting factor. In the clinical trials, participants with FIX levels below 2% (of normal) receive a single gene therapy infusion. The results of the trials have so far shown that patients given etranacogene dezaparvovec have continuous production of FIX, whereby they have reported much less bleeding and factor treatment. Questions relating to the safety of the gene therapy and how long it works will hopefully be answered through long-term follow-up of the patients once the trials are completed.

scholarly journals Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease

2018 ◽  
Vol 29 (3) ◽  
pp. 148-155 ◽  
Author(s):  
Stéphane Palfi ◽  
Jean Marc Gurruchaga ◽  
Hélène Lepetit ◽  
Katy Howard ◽  
G. Scott Ralph ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Phase I ◽  
Lentiviral Vector ◽  
Long Term Follow Up

Pomalidomide Therapy for Myelofibrosis: Analysis of Results From Three Consecutive Clinical Trials

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1759-1759 ◽  
Author(s):  
Kebede Begna ◽  
Animesh Pardanani ◽  
Ruben A. Mesa ◽  
William J Hogan ◽  
Mark R. Litzow ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Costal Margin ◽  
Median Response ◽  
Long Term Treatment

Abstract Abstract 1759 Background: Pomalidomide is a second generation IMiDsÒ immunomodulatory drug that has been shown to be active in the treatment of myelofibrosis (MF)-associated anemia (J Clin Oncol 2009; 27: 4563; Leukemia 2011;25: 301). In the current sponsor-independent analysis, we report long-term follow up data on patients from the Mayo Clinic who had participated in three consecutive clinical trials using single agent pomalidomide for MF. Methods: From May 2007 to January 2010, 94 patients with MF (including primary and post-polycythemia/essential thrombocythemia) were enrolled in three consecutive phase I and II clinical trials involving pomalidomide with or without prednisone. Eight two patients who received only single agent pomalidomide constitute the study population for the current study. Follow up information was updated in July, 2011. Results: Among the 82 study patients, 19 were included in a phase I dose escalation study (2.5-3.5 mg/day), 58 in a phase II low-dose single agent pomalidomide study (0.5 mg/day), and 5 in a phase II randomized study (2 mg/day). Median age was 67 years and 63 (77 %) patients were red blood cell transfusion dependent at study entry. Forty-five (55%), 24 (29%), 7 (9%), and 2 (2%) patients remained on pomalidomide therapy for at least 6, 12, 24, and 36 months, respectively (Table 1). The overall anemia response rate per IWG-MRT criteria was 27% (22/82). Response occurred in the first 6 months in 21 (96%) of the 22 responders. The median time for response was 2.3 months (range, 1–10). The median response duration was 16.5 months (2–40). The anemia response rate in patients with spleen size palpable at less than 10 cm below the costal margin was 44 % (17/39) vs. 10 % (4/39) in those whose spleen was palpable at or above 10 cm (p=0.002). The anemia response rate was twice as likely in JAK2 mutated versus non-mutated cases (30% vs 15% p=0.2). Anemia response rate was also higher in patients with at least 50% increase in absolute basophil count during the first month of therapy: 39% (19/49) vs 6% (2/32) p=0.001). The anemia response rate was not significantly affected by karyotype, transfusion need or leukocyte count. Among the anemia responders (n=22), 3 (14%) relapsed in the first 12 months; relapse was more likely in the presence of baseline leukocytosis (p=0.006). Among the 24 patients who took pomalidomide for at lease 12 months, grade 1 sensory neuropathy developed in 4 (16%) patients. Conclusion: Anemia response to pomalidomide therapy in myelofibrosis often occurs in the first 6 months of treatment and is more likely to occur in the presence of JAK2V617F and absence of marked splenomegaly. Long-term treatment with pomalidomide might be associated with sensory peripheral neuropathy in a subset of treated patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Gene Therapy ◽  
2021 ◽  
Author(s):  
Aleksi J. Leikas ◽  
Iiro Hassinen ◽  
Antti Hedman ◽  
Antti Kivelä ◽  
Seppo Ylä-Herttuala ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase I ◽  
Myocardial Perfusion Reserve ◽  
Control Group ◽  
Cardiovascular Adverse Event ◽  
Safety And Efficacy ◽  
Perfusion Reserve ◽  
Canadian Cardiovascular Society Class

AbstractIn phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3–10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36–2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

scholarly journals Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis

2021 ◽  
pp. 135245852110002
Author(s):  
Bruce AC Cree ◽  
Jeffrey A Cohen ◽  
Anthony T Reder ◽  
Davorka Tomic ◽  
Diego Silva ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Therapeutic Benefit ◽  
Disease Modifying Therapies ◽  
Long Term Follow Up ◽  
Post Hoc ◽  
Switch Group ◽  
Relevant Outcome

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

Exercise and Osteoarthritis: Are We Stopping Too Early? Findings from the Clearwater Exercise Study

2006 ◽  
Vol 14 (2) ◽  
pp. 169-180 ◽  
Author(s):  
Frances V. Wilder ◽  
John P. Barrett ◽  
Edward J. Farina
Keyword(s):  
Clinical Trials ◽  
Knee Pain ◽  
Exercise Intervention ◽  
Pain Reduction ◽  
Optimal Length ◽  
Knee Oa ◽  
Pain Scores ◽  
Time Periods

The value of exercise for people with knee osteoarthritis (OA) receives continuing consideration. The optimal length of study follow-up time remains unclear. A group of individuals with knee OA participating in an exercise intervention was followed for 2 years. The authors quantified the change in knee-pain scores during Months 1–12 and during Months 13–24. Eleven individuals with radiographic knee OA and knee-pain scores of 2+ were evaluated. Pain scores were collected weekly from participants who exercised three times a week. Participants demonstrated pain reduction during both time periods. Pain reduction during Months 13–24, –10.7%, was slightly higher than pain reduction during Months 1–12, –7.8%. Among people with knee OA who exercise, these findings suggest that knee-pain amelioration continues beyond 12 months. Clinicians should consider encouraging long-term exercise programs for knee-OA patients. To best characterize the effect of exercise on knee pain, researchers designing clinical trials might want to lengthen the studies’ duration.

The Challenge of Follow-Up for Clinical Trials of Somatic Gene Therapy

1992 ◽  
Vol 3 (6) ◽  
pp. 657-663 ◽  
Author(s):  
Fred D. Ledley ◽  
Baruch Brody ◽  
Claudia A. Kozinetz ◽  
Susan G. Mize
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Somatic Gene Therapy ◽  
Somatic Gene
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