Objectives Genetic therapies replace or inactivate disease-causing genes or introduce new or modified genes. These therapies have the potential to cure in a single application rather than treating symptoms through repeated administrations. This evidence map provides a broad overview of the genetic therapies that have been evaluated in randomised controlled trials (RCTs) for efficacy and safety. Eligibility criteria Two independent reviewers screened publications using predetermined eligibility criteria. Study details and data on safety and efficacy were abstracted from included trials. Results were visualised in an evidence map. Information sources We searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov and grey literature to November 2018. Risk of bias Only RCTs were included in this review to reduce the risk of selection bias in the evaluation of genetic therapy safety and efficacy. Included studies We identified 119 RCTs evaluating genetic therapies for a variety of clinical conditions. Synthesis of results On average, samples included 107 participants (range: 1–1022), and were followed for 15 months (range: 0–124). Interventions using adenoviruses (40%) to treat cardiovascular diseases (29%) were the most common. Description of the effect In RCTs reporting safety and efficacy outcomes, in the majority (60%) genetic therapies were associated with improved symptoms but in nearly half (45%) serious adverse event (SAEs) were also reported. Improvement was reported in trials treating cancer, cardiovascular, ocular and muscular diseases. However, only 19 trials reported symptom improvement for at least 1 year. Strengths and limitations of evidence This is the first comprehensive evidence map of RCTs evaluating the safety and efficacy of genetic therapies. Evidence for long-term effectiveness and safety is still sparse. This lack of evidence has implications for the use, ethics, pricing and logistics of genetic therapies. Interpretation This evidence map provides a broad overview of research studies that allow strong evidence statements regarding the safety and efficacy of genetic therapies. Most interventions improve symptoms, but SAE are also common. More research is needed to evaluate genetic therapies with regard to the potential to cure diseases.

https://ebm.bmj.com/content/ebmed/early/2020/11/09/bmjebm-2020-111448.full.pdf

An evidence map of randomised controlled trials evaluating genetic therapies.

Nanoparticle-based delivery systems such as RNA-encapsulating lipid nanoparticles (RNA LNPs) have dramatically advanced in function and capacity over the last few decades. RNA LNPs boast of a diverse array of external and core configurations that enhance targeted delivery and prolong circulatory retention, advancing therapeutic outcomes. Particularly within the realm of cancer immunotherapies, RNA LNPs are increasingly gaining prominence. Pre-clinical in vitro and in vivo studies have laid a robust foundation for new and ongoing clinical trials that are actively enrolling patients for RNA LNP cancer immunotherapy. This review explores RNA LNPs, starting from their core composition to their external membrane formulation, set against a backdrop of recent clinical breakthroughs. We further elucidate the LNP delivery avenues, broach the prevailing challenges, and contemplate the future perspectives of RNA LNP-mediated immunotherapy. 

RNA-encapsulating lipid nanoparticles in cancer immunotherapy: From pre-clinical studies to clinical trials.

Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer.

Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation

LBA53 A phase II, randomised, open-label study of gemcitabine/carboplatin first-line chemotherapy in combination with or without the antisense oligonucleotide apatorsen (OGX-427) in advanced squamous cell lung cancers.

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LBA53 A phase II, randomised, open-label study of gemcitabine/carboplatin first-line chemotherapy in combination with or without the antisense oligonucleotide apatorsen (OGX-427) in advanced squamous cell lung cancers.