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The Progression of Treatment for Refractory Hypercholesterolemia: Focus on the Prospect of Gene Therapy.

ABSTRACT: Refractory hypercholesterolemia (RH), including homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia, is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) despite existing cholesterol-lowering methods at maximal tolerable doses. Patients with RH have early onset and higher risk of atherosclerotic cardiovascular disease (ASCVD) under insufficient treatment. Therefore, it is urgent to seek new therapies to maintain the blood lipids in refractory hyperlipidemia at normal levels. Currently, new cholesterol-lowering strategies are on the market, not only at the protein level [i.e., bempedoic acid (inhibiting ATP-citrate lyase), alirocumab and evolocumab (monoclonal antibodies against PCSK9), evinacumab (monoclonal antibody against ANGPTL3)] but also at the transcript level [i.e., mipomersen (antisense oligonucleotide inhibiting ApoB), inclisiran (siRNA targeting PCSK9)], providing more options for RH patients to achieve their lipid-lowering targets. More RNA-based therapies targeting RH-related genes have been designed for the treatment. However, for a proportion of patients, especially those with LDLR deficiency, the available treatments are still insufficient. More recently, emerging genome engineering based on CRISPR/Cas9 techniques, and advanced delivery technologies such as lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, lipid nanoparticles, and exosomes are being rapidly developed and implemented as novel therapies for RH. Gene therapy targeting RH-related genes has been successfully conducted in cells, mice, and non-human primates with high efficacy in lipid lowering and good tolerability. Especially the new generation of genome editing technique, base editing, performed in vivo with ideal lipid-lowering effect and limited occurrence of unwanted results. Excitingly, a phase I/II clinical study of LDLR gene replacement has been recently completed in RH patients, likely to be employed in clinical practice in the future. Furthermore, new targets for cholesterol reduction such as REV-ERB, G protein-coupled receptor, Ubiquitin specific peptidase 20 are continually being developed. This narrative review updates recent advances in treatment for RH, summarizes related clinical trials and preclinical studies, especially on the prospect of gene therapy.

SUBMITTER: Li ZF

PROVIDER: S-EPMC9218664 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been tailored specifically to the demands of patients with persistent depressive disorder (PDD). According to the CBASP model, PDD patients are supposed to live perceptually disconnected from their social environment, which consequently maintains depression. While initially developed as an individual treatment modality, the adaptation for group therapy yields an important interpersonal space. However, little is known about the specific factors that contribute to patients' benefit from the CBASP group modality. Methods: The analyzed sample comprised N = 87 PDD patients who completed a 12 week multimodal inpatient treatment including 2 weekly CBASP-specific individual and group sessions, respectively, as well as CBASP-unspecific medical contacts, pharmacotherapy and complementary therapies. Group sessions included trainings in situational analysis and interpersonal skills. Interpersonal change over therapy was examined based on the patients' self-perceived interpersonal problems (IIP) and the impact messages as perceived by their individual therapists (IMI). Pre and post-treatment data were compared using within-sample t-tests. Additionally, patients evaluated CBASP group therapy on a feedback form. They were invited to reflect on individual benefits and its helpful and unhelpful aspects. Qualitative content analysis with inductive category development was used to analyze feedback. Inter-rater reliability was computed to confirm categories before summarizing the frequencies of reported factors. Results: Self-perceived interpersonal distress significantly decreased over therapy. Patients reported reduced interpersonal problems and therapists reported more friendly and dominant impact messages. Interestingly, patients who showed a significant depressive symptom reduction described higher change scores. Regarding qualitative data, patients reported five main benefits from group therapy: Gain in social competence, self-confidence, self-reflection, interpersonal dynamics, and optimism/universality. Patients responding to CBASP identified significantly more factors than non-responders. Conclusions: Compared to studies with individual CBASP only, the present findings suggest that CBASP group therapy may contribute to the improvement of interpersonal behavior. Group therapy is discussed as a potential boosting effect for individual CBASP. However, as the present data were collected in a multimodal inpatient setting without competitor, randomized controlled trials are warranted that investigate the specific benefits of the group modality or the combined individual and group therapy over individual CBASP only.

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The Progression of Treatment for Refractory Hypercholesterolemia: Focus on the Prospect of Gene Therapy.

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