Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review

Neurocognitive adverse events have been observed with the widespread use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or “statins,” which reduce low-density lipoprotein cholesterol (LDL-C) levels and subsequently cardiovascular risk. The United States Food and Drug Association directed manufacturers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to monitor for neurocognitive adverse events due to their potent effects on LDL-C reduction, which is a proposed mechanism for neuronal cell dysfunction. Other proposed mechanisms for PCSK9 inhibitor-associated neurocognitive adverse events include N-methyl-d-aspartate receptor modulation, dysregulation of lipid and glucose metabolism, and patient-specific risk factors for cognitive impairment. The purpose of this narrative review article is to describe the proposed mechanisms, incidence of neurocognitive adverse events from phase II and III trials for PCSK9 inhibitors, neurocognitive assessments utilized in clinical trials, and clinical implications. Given the increasing prevalence of PCSK9 inhibitor use and the neurocognitive adverse events observed with prior lipid-lowering therapies, clinicians should be aware of the risks associated with PCSK9 inhibitors, especially when therapy is indicated for patients at high risk for cardiovascular events. Overall, the incidence of PCSK9 inhibitor-associated neurocognitive appears to be uncommon. However, additional prospective studies evaluating cognitive impairment may be beneficial to determine the long-term safety of these agents.

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Gene Therapy in Hemophilia: Recent Advances

International Journal of Molecular Sciences ◽

10.3390/ijms22147647 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7647

Author(s):

E. Carlos Rodríguez-Merchán ◽

Juan Andres De Pablo-Moreno ◽

Antonio Liras

Keyword(s):

Gene Therapy ◽

Adverse Events ◽

Factor Viii ◽

Coagulation Factor ◽

Cost Savings ◽

Factor Ix ◽

Clotting Factors ◽

Advanced Therapies ◽

Potential Benefits

Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.

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Managing adverse events after endoscopic ultrasound‐guided (EUS) drainage of the biliary tract and pancreatic fluid collections: a narrative review (with video)

Digestive Endoscopy ◽

10.1111/den.14080 ◽

2021 ◽

Author(s):

Mateus Pereira Funari ◽

Igor Braga Ribeiro ◽

Marcos Eduardo Lera dos Santos ◽

Sergio Eiji Matuguma ◽

Eduardo Guimarães Hourneaux de Moura

Keyword(s):

Adverse Events ◽

Biliary Tract ◽

Endoscopic Ultrasound ◽

Narrative Review ◽

Ultrasound Guided ◽

Pancreatic Fluid Collections ◽

Pancreatic Fluid ◽

Fluid Collections

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SGLT2 inhibitors: a narrative review of efficacy and safety

Journal of Osteopathic Medicine ◽

10.1515/jom-2020-0153 ◽

2021 ◽

Vol 121 (2) ◽

pp. 229-239

Author(s):

Donald S. Nelinson ◽

Jose M. Sosa ◽

Robert J. Chilton

Keyword(s):

Adverse Events ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Narrative Review ◽

Atherosclerotic Cardiovascular Disease ◽

Comorbid Conditions ◽

Postprandial Plasma Glucose ◽

Renal Outcomes ◽

Glucose Levels ◽

Wide Range

Abstract Type 2 diabetes mellitus (T2DM) is a cardio-renal-metabolic condition that is frequently associated with multiple comorbidities, including atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD). The sodium-glucose co-transporter-2 (SGLT2) inhibitors, which lower glycated hemoglobin, fasting and postprandial plasma glucose levels, body weight, and blood pressure, as well as reduce the risk of a range of cardiovascular and renal outcomes without increasing hypoglycaemic risk, have heralded a paradigm shift in the management of T2DM. These drugs are compatible with most other glucose-lowering agents and can be used in patients with a wide range of comorbid conditions, including ASCVD, HF, and CKD, and in those with estimated glomerular filtration rates as low as 30 mL/min/1.73 m2. However, there are misunderstandings surrounding the clinical implications of SGLT2 inhibitors’ mechanism of action and concerns about the key adverse events with which this class of drugs has been associated. This narrative review summarizes the data that support the efficacy of SGLT2 inhibitors in reducing the risks of cardiovascular and renal outcomes in patients with T2DM and comorbid conditions and clarifies information relating to SGLT2 inhibitor-related adverse events.

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Ocular Inflammation and Treatment Emergent Adverse Events in Retinal Gene Therapy

International Ophthalmology Clinics ◽

10.1097/iio.0000000000000366 ◽

2021 ◽

Vol 61 (3) ◽

pp. 151-177

Author(s):

Neesurg Mehta ◽

Deborah A. Robbins ◽

Glenn Yiu

Keyword(s):

Gene Therapy ◽

Adverse Events ◽

Ocular Inflammation ◽

Retinal Gene Therapy

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Gene Therapy for Retinal Diseases

Essentials in Ophthalmology - Advances in Vision Research, Volume III ◽

10.1007/978-981-15-9184-6_30 ◽

2021 ◽

pp. 435-454

Author(s):

Chitra Gopinath ◽

Subhradeep Sarkar ◽

Arkasubhra Ghosh

Keyword(s):

Gene Therapy ◽

Retinal Diseases

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Sight of Action: the Rationale and Evolution of Gene Therapy Approaches to the Treatment of Retinal Diseases

Current Ophthalmology Reports ◽

10.1007/s40135-020-00255-9 ◽

2020 ◽

Vol 8 (4) ◽

pp. 267-280

Author(s):

Kathryn W. Woodburn ◽

Sharmila Vijay ◽

Mark S. Blumenkranz

Keyword(s):

Gene Therapy ◽

Retinal Diseases

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The FDA's Proposal for Public Disclosure of Adverse Events in Gene Therapy Trials

Politics and the Life Sciences ◽

10.1017/s0730938400014866 ◽

2000 ◽

Vol 19 (2) ◽

pp. 261-268

Author(s):

Deborah R. Barnbaum

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Informed Consent ◽

Adverse Events ◽

Drug Administration ◽

Food And Drug Administration ◽

Public Disclosure

In January 2001, the Food and Drug Administration (FDA) proposed annual public disclosure of adverse events during gene therapy and xenotransplantation trials. The proposed policy raises the following questions: (1) Is the reformed policy in accord with the FDA's long-standing informed consent policies? (2) Why pair gene therapy trials and xenotransplantation trials in the revised guidelines? (3) Why single out these trials for public disclosure of adverse events? Each question is examined, and three conclusions are drawn. First, the FDA's own policies on informed consent require prompter public disclosure of adverse events. Second, the coupling of gene therapy and xenotransplantation trials entails a conceptual mistake in the types of communities that are harmed by each therapy's related adverse events. Third, all clinical trials merit such public disclosure of adverse events, not only gene therapy and xenotransplantation trials.

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