The Limitless Future of RNA Therapeutics

Recent advances in the generation, purification and cellular delivery of RNA have enabled development of RNA-based therapeutics for a broad array of applications. RNA therapeutics comprise a rapidly expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. In this review we discuss general concepts of different classes of RNA-based therapeutics, including antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and messenger RNA. Furthermore, we provide an overview of the RNA-based therapies that are currently being evaluated in clinical trials or have already received regulatory approval. The challenges and advantages associated with use of RNA-based drugs are also discussed along with various approaches for RNA delivery. In addition, we introduce a new concept of hospital-based RNA therapeutics and share our experience with establishing such a platform at Houston Methodist Hospital.

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CURATE.AI: Optimizing Personalized Medicine with Artificial Intelligence

SLAS TECHNOLOGY Translating Life Sciences Innovation ◽

10.1177/2472630319890316 ◽

2019 ◽

Vol 25 (2) ◽

pp. 95-105

Author(s):

Agata Blasiak ◽

Jeffrey Khong ◽

Theodore Kee

Keyword(s):

Clinical Trials ◽

Personalized Medicine ◽

Standard Of Care ◽

Small Data ◽

Current Standard ◽

Dose Selection ◽

Support Tool ◽

Combination Treatments ◽

Multiple Challenges ◽

Over Time

The clinical team attending to a patient upon a diagnosis is faced with two main questions: what treatment, and at what dose? Clinical trials’ results provide the basis for guidance and support for official protocols that clinicians use to base their decisions upon. However, individuals rarely demonstrate the reported response from relevant clinical trials, often the average from a group representing a population or subpopulation. The decision complexity increases with combination treatments where drugs administered together can interact with each other, which is often the case. Additionally, the individual’s response to the treatment varies over time with the changes in his or her condition, whether via the indication or physiology. In practice, the drug and the dose selection depend greatly on the medical protocol of the healthcare provider and the medical team’s experience. As such, the results are inherently varied and often suboptimal. Big data approaches have emerged as an excellent decision-making support tool, but their application is limited by multiple challenges, the main one being the availability of sufficiently big datasets with good quality, representative information. An alternative approach—phenotypic personalized medicine (PPM)—finds an appropriate drug combination (quadratic phenotypic optimization platform [QPOP]) and an appropriate dosing strategy over time (CURATE.AI) based on small data collected exclusively from the treated individual. PPM-based approaches have demonstrated superior results over the current standard of care. The side effects are limited while the desired output is maximized, which directly translates into improving the length and quality of individuals’ lives.

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The South African macular oedema in diabetics study (the same study): a prospective randomized non-inferiority trial

International Journal of Clinical Trials ◽

10.18203/2349-3259.ijct20204483 ◽

2020 ◽

Vol 7 (4) ◽

pp. 255

Author(s):

Naseer Ally ◽

Sarah Ismail ◽

Bongi P. Sithole ◽

Mpho Tsimanyane ◽

Ismail Mayet ◽

...

Keyword(s):

Clinical Trials ◽

Macular Oedema ◽

Diabetic Macular Oedema ◽

Cost Effective ◽

Standard Of Care ◽

Current Standard ◽

Treat And Extend ◽

Anti Vegf ◽

Trial Testing ◽

Pro Re Nata

Background: Diabetic retinopathy is the most common cause of visual loss affecting the economically productive age group globally. Diabetic macular oedema (DMO) results from leakage of fluid into the retinal interstitial space. Anti-vascular endothelial growth factor (anti-VEGF) drugs are the first line treatment for DMO. Since monthly injections are required, this treatment regimen can prove very costly. Of the anti-VEGF drugs, bevacizumab is the most cost-effective. The pro re nata (PRN) method is the current standard of care. However, the treat and extend (T and E) regimen can potentially decrease the patient burden on hospitals. Thus far, no randomised clinical trials have been performed using Bevacizumab in a treat and extend versus pro re nata regimen.Methods: A prospective randomised non-inferiority clinical trial testing bevacizumab (1.25 mg) in a treat and extend method versus the pro re nata method is being conducted. Patients will be randomised using a simple computer-based randomised algorithm. The primary outcome is non-inferiority within a five-letter margin for the T and E regimen versus the PRN regimen.Conclusions: This study aims to inform a key area in the literature on the treatment of DMO, i.e. whether a T and E regimen is non-inferior to a PRN regimen in the treatment of DMO with bevacizumab, which is the only anti VEGF available in resource poor settings. It is motivated by the cost involved in the treatment of DMO as well as the treatment burden on both the patient and the health institution at which the patient is receiving treatment.Trial registration: The trial has been registered on the Pan-African clinical trials registry (PACTR202001624880-753).

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Recent Advances in Oligonucleotide Therapeutics in Oncology

International Journal of Molecular Sciences ◽

10.3390/ijms22073295 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3295

Author(s):

Haoyu Xiong ◽

Rakesh N. Veedu ◽

Sarah D. Diermeier

Keyword(s):

Clinical Trials ◽

Antisense Oligonucleotides ◽

Causes Of Death ◽

Survival Rates ◽

Cancer Recurrence ◽

Small Interfering Rnas ◽

The Past ◽

Oncology Review ◽

Recent Developments ◽

Review Current

Cancer is one of the leading causes of death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types of cancer over the past decades. However, cancer recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, and aptamers, show promising clinical outcomes for disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, and macular degeneration. While no approved oligonucleotide drug currently exists for any type of cancer, results obtained in preclinical studies and clinical trials are encouraging. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in oncology, review current clinical trials, and discuss associated challenges.

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Current RNA-based Therapeutics in Clinical Trials

Current Gene Therapy ◽

10.2174/1566523219666190719100526 ◽

2019 ◽

Vol 19 (3) ◽

pp. 172-196 ◽

Cited By ~ 15

Author(s):

Ling-Yan Zhou ◽

Zhou Qin ◽

Yang-Hui Zhu ◽

Zhi-Yao He ◽

Ting Xu

Keyword(s):

Clinical Trials ◽

Rapid Development ◽

Genetic Diseases ◽

Three Dimensional ◽

Therapeutic Effects ◽

Messenger Rnas ◽

Small Interfering Rnas ◽

Rna Modifications ◽

Guide Rna ◽

Endogenous Genes

Long-term research on various types of RNAs has led to further understanding of diverse mechanisms, which eventually resulted in the rapid development of RNA-based therapeutics as powerful tools in clinical disease treatment. Some of the developing RNA drugs obey the antisense mechanisms including antisense oligonucleotides, small interfering RNAs, microRNAs, small activating RNAs, and ribozymes. These types of RNAs could be utilized to inhibit/activate gene expression or change splicing to provide functional proteins. In the meantime, some others based on different mechanisms like modified messenger RNAs could replace the dysfunctional endogenous genes to manage some genetic diseases, and aptamers with special three-dimensional structures could bind to specific targets in a high-affinity manner. In addition, the recent most popular CRISPR-Cas technology, consisting of a crucial single guide RNA, could edit DNA directly to generate therapeutic effects. The desired results from recent clinical trials indicated the great potential of RNA-based drugs in the treatment of various diseases, but further studies on improving delivery materials and RNA modifications are required for the novel RNA-based drugs to translate to the clinic. This review focused on the advances and clinical studies of current RNA-based therapeutics, analyzed their challenges and prospects.

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Alexander Technique vs. Targeted Exercise for Neck Pain—A Preliminary Comparison

Applied Sciences ◽

10.3390/app11104640 ◽

2021 ◽

Vol 11 (10) ◽

pp. 4640

Author(s):

Jordan J. Becker ◽

Tara L. McIsaac ◽

Shawn L. Copeland ◽

Rajal G. Cohen

Keyword(s):

Neck Pain ◽

Video Game ◽

Cost Effective ◽

Standard Of Care ◽

Chronic Neck Pain ◽

Exercise Group ◽

Alexander Technique ◽

Private Lessons ◽

Pain Disability ◽

Exercise Class

Background: Alexander technique private lessons have been shown to reduce chronic neck pain and are thought to work by different mechanisms than exercise. Group classes may also be effective and would be cost-effective. Design: A two-group pre-test/post-test design. Participants were assigned to either a general Alexander technique class or an exercise class designed to target neck pain. Both groups met over 5 weeks for two 60 min sessions/week. Participants: A total of 16 participants with chronic neck pain (aged 50+/−16 years) completed this study. Interventions: The Alexander class used awareness-building methods to teach participants to reduce habitual tension during everyday activities. The exercise class was based on physical therapy standard of care to strengthen neck and back muscles thought to be important for posture. Measures: We assessed neck pain/disability, pain self-efficacy, activation of the sternocleidomastoid muscles during the cranio-cervical flexion test, and posture while participants played a video game. Results: Both groups reported decreased neck pain/disability after the interventions. Sternocleidomastoid activation decreased only in the Alexander group. Conclusion: In this small preliminary study, Alexander classes were at least as effective as exercise classes in reducing neck pain and seemed to work via a different mechanism. Larger, multi-site studies are justified.

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Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

Pharmaceuticals ◽

10.3390/ph14010051 ◽

2021 ◽

Vol 14 (1) ◽

pp. 51

Author(s):

Brinda Balasubramanian ◽

Simran Venkatraman ◽

Kyaw Zwar Myint ◽

Tavan Janvilisri ◽

Kanokpan Wongprasert ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Drug Development ◽

Surgical Resection ◽

Treatment Options ◽

Standard Of Care ◽

Time Data ◽

Current Standard ◽

Innovative Drug ◽

Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

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Rationalisations for women-only randomised controlled trials in conditions that affect both sexes: a scoping review protocol

BMJ Open ◽

10.1136/bmjopen-2020-043370 ◽

2021 ◽

Vol 11 (2) ◽

pp. e043370

Author(s):

Ainsley Matthewson ◽

Olena Bereznyakova ◽

Brian Dewar ◽

Alexandra Davis ◽

Mark Fedyk ◽

...

Keyword(s):

Clinical Trials ◽

Scoping Review ◽

Randomised Controlled Trials ◽

Standard Of Care ◽

Standards Of Care ◽

Controlled Trials ◽

Theory Approach ◽

Reference Centre ◽

Cochrane Database ◽

Randomised Controlled

IntroductionWomen have historically been under-represented in randomised controlled trials (RCTs), including many landmark RCTs that established standards of care. In light of this fact, some modern researchers are calling for replication of earlier landmark trials with women only. This approach is ethically concerning, in that it would require some enrolled women to be deprived of treatments that are currently considered standard of care.ObjectiveIn an attempt to better understand the justification of a women-only approach to designing clinical trials, this study looks to systematically categorise the number of women-only RCTs for conditions that affect both men and women and the reasons given within the medical and philosophical literatures to perform them.MethodologyThis scoping review of the literature will search, screen and select articles based on predetermined inclusion/exclusion criteria, after which a grounded theory approach will be used to synthesise the data. It is expected that there will be a variety of reasons given for why a women-only trial may be justified. Electronic databases that will be searched include MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trials Register, Web of Science Proceedings, ClinicalTrials.gov, Philosopher’s Index, Phil Papers, JSTOR, Periodicals Archive Online, Project MUSE and the National Reference Centre for Bioethics.SignificanceThe scope of this study is to determine published rationales used to justify women-only randomised trials, both in the case of new trials and in the repetition of landmark trials.Ethics and disseminationResearch ethics board approval is not required for this study as there is no participant involvement. Results will be published as a stand-alone manuscript and will inform a larger project related to the ethics of a women-only RCT of carotid intervention for women with symptomatic high-grade carotid stenosis.

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Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05208-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Roland Roelz ◽

Fabian Schubach ◽

Volker A. Coenen ◽

Carolin Jenkner ◽

Christian Scheiwe ◽

...

Keyword(s):

Clinical Trials ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Neurological Outcome ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Standard Of Care ◽

Secondary Brain Injury ◽

Ringer’S Solution ◽

Randomized Controlled ◽

Therapy Protocol

Abstract Background Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH. Methods This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints. Discussion New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution. Trial registration Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645. Registered on 8 May 2019

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National control laboratory independent lot testing of COVID-19 vaccines: the UK experience

npj Vaccines ◽

10.1038/s41541-021-00368-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Nicola J. Rose ◽

Paul Stickings ◽

Silke Schepelmann ◽

Marc J. A. Bailey ◽

Chris Burns

Keyword(s):

Clinical Trials ◽

Vaccine Development ◽

Regulatory Approval ◽

Safety Measures ◽

Discovery Research ◽

Innovative Products ◽

The Uk ◽

Vaccine Availability ◽

And Control

AbstractThe past 18 months have seen an unprecedented approach to vaccine development in the global effort against the COVID-19 pandemic. The process from discovery research, through clinical trials and regulatory approval often takes more than 10 years. However, the critical need to expedite vaccine availability in the pandemic has meant that new approaches to development, manufacturing, and regulation have been required: this has necessitated many stages of product development, clinical trials, and manufacturing to be undertaken in parallel at a global level. Through the development of these innovative products, the world has the best chance of finding individual, or combinations of, vaccines that will provide adequate protection for the world’s population. Despite the huge scientific and regulatory achievements and significant investment to accelerate vaccine availability, it is essential that safety measures are not compromised. Here we focus on the post regulatory approval testing by independent laboratories that provides an additional assurance of the safety and quality of a product, with an emphasis on the UK experience through the National Institute for Biological Standards and Control (NIBSC), an expert centre of the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).

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