Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Mapping Intimacies ◽

10.20944/preprints202111.0084.v1 ◽

2021 ◽

Author(s):

Jannik Prasuhn ◽

Norbert Brüggemann

Keyword(s):

Mitochondrial Dysfunction ◽

Disease Onset ◽

Treatment Strategies ◽

Mitochondrial Diseases ◽

Therapeutic Approaches ◽

Treatment Target ◽

Gene Therapies ◽

Parkinsonian Disorders ◽

Potential Strategy ◽

Viable Treatment

Background. Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods. This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results. Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions. Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

Download Full-text

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Genes ◽

10.3390/genes12111840 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1840

Author(s):

Jannik Prasuhn ◽

Norbert Brüggemann

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Disease Onset ◽

Treatment Strategies ◽

Mitochondrial Diseases ◽

Therapeutic Approaches ◽

Gene Therapies ◽

Parkinsonian Disorders ◽

Viable Treatment

Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

Download Full-text

The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽

10.3390/life11070648 ◽

2021 ◽

Vol 11 (7) ◽

pp. 648

Author(s):

Andrea L. Reid ◽

Matthew S. Alexander

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mitochondrial Dysfunction ◽

Disease Onset ◽

Exon Skipping ◽

Dystrophin Gene ◽

Muscle Disease ◽

Mitochondrial Morphology ◽

Gene Therapies ◽

Dystrophin Protein

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

Download Full-text

Nanostructured Hyaluronic Acid-based Materials for the Delivery of siRNA

Current Pharmaceutical Design ◽

10.2174/1381612824666180807123705 ◽

2018 ◽

Vol 24 (23) ◽

pp. 2678-2691 ◽

Cited By ~ 4

Author(s):

Keval Shah ◽

Sunita Chawla ◽

Anuradha Gadeval ◽

Goutham Reddy ◽

Rahul Maheshwari ◽

...

Keyword(s):

Hyaluronic Acid ◽

Rna Interference ◽

Sirna Delivery ◽

Treatment Strategies ◽

Aqueous Solubility ◽

Micro Rna ◽

Target Space ◽

Significant Progress ◽

Gene Therapies ◽

Future Potential

Background: The search for the effective treatment strategies to combat a disease that is characterized by abnormal cell growth and known as cancer is still required to reach its destiny. To address the problem, recently several gene therapies based on novel RNA interference (RNAi) have been proposed such as siRNA, micro RNA, shRNA, etc. out of which, siRNAs (silencing RNA) promises to show significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility of treating cancer. Methods: This review aims to uncover the hyaluronic acid (HA) and HA-hybridized nanoplatforms for siRNA delivery systems with a particular focus on the discussion of available reports while addressing the future potential of HA-based treatment strategies. Results: HA modified siRNA delivery, as promised, provided better targeting potential in many types of cancers. In addition, it was able to modify the release of siRNA as well. Toxicity of HA is well mentioned however, the loophole is yet to be filled by exploring various remedies for overcoming toxicity. Conclusion: To overcome the problems associated with these emerging genetic tools, investigators have employed glycosaminoglycan HA-based biopolymers. This biopolymer offers a variety of properties such as biodegradability, biocompatibility, aqueous solubility, viscoelasticity, and non-immunogenicity.

Download Full-text

Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽

10.3390/children8070532 ◽

2021 ◽

Vol 8 (7) ◽

pp. 532

Author(s):

Dorota Wesół-Kucharska ◽

Dariusz Rokicki ◽

Aleksandra Jezela-Stanek

Keyword(s):

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Clinical Picture ◽

Poor Prognosis ◽

Treatment Options ◽

Mitochondrial Diseases ◽

Energy Deficit ◽

Atp Production ◽

Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

Download Full-text

B Cell Metabolism and Autophagy in Autoimmunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.681105 ◽

2021 ◽

Vol 12 ◽

Author(s):

Iwan G. A. Raza ◽

Alexander J. Clarke

Keyword(s):

B Cells ◽

Autoimmune Diseases ◽

B Cell ◽

Antigen Presentation ◽

Functional Properties ◽

Cell Metabolism ◽

Metabolic Phenotype ◽

Therapeutic Approaches ◽

Treatment Target ◽

Development And Differentiation

B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.

Download Full-text

Gene Therapy for Pancreatic Diseases: Current Status

International Journal of Molecular Sciences ◽

10.3390/ijms19113415 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3415 ◽

Cited By ~ 4

Author(s):

Kenya Kamimura ◽

Takeshi Yokoo ◽

Shuji Terai

Keyword(s):

Pancreatic Cancer ◽

The Body ◽

Therapeutic Options ◽

Current Status ◽

Endocrine Tumors ◽

Therapeutic Approaches ◽

Islet Cell Tumors ◽

Pancreatic Diseases ◽

Gene Therapies ◽

New Strategies

The pancreas is a key organ involved in digestion and endocrine functions in the body. The major diseases of the pancreas include pancreatitis, pancreatic cancer, cystic diseases, pancreatic divisum, islet cell tumors, endocrine tumors, diabetes mellitus, and pancreatic pain induced by these diseases. While various therapeutic methodologies have been established to date, however, the improvement of conventional treatments and establishment of novel therapies are essential to improve the efficacy. For example, conventional therapeutic options, including chemotherapy, are not effective against pancreatic cancer, and despite improvements in the last decade, the mortality rate has not declined and is estimated to become the second cause of cancer-related deaths by 2030. Therefore, continuous efforts focus on the development of novel therapeutic options. In this review, we will summarize the progress toward the development of gene therapies for pancreatic diseases, with an emphasis on recent preclinical studies and clinical trials. We aim to identify new areas for improvement of the current methodologies and new strategies that will lead to safe and effective gene therapeutic approaches in pancreatic diseases.

Download Full-text

Treatment strategies for protein-losing enteropathy in Fontan-palliated patients

Cardiology in the Young ◽

10.1017/s1047951120000864 ◽

2020 ◽

Vol 30 (5) ◽

pp. 698-709

Author(s):

Anastasia Schleiger ◽

Stanislav Ovroutski ◽

Björn Peters ◽

Stephan Schubert ◽

Joachim Photiadis ◽

...

Keyword(s):

Cardiac Transplantation ◽

Fontan Procedure ◽

Disease Onset ◽

Treatment Strategies ◽

Individual Treatment ◽

Interventional Treatment ◽

Vasodilator Therapy ◽

Protein Losing Enteropathy ◽

Pulmonary Vasodilator

AbstractObjective:Protein-losing enteropathy is an infrequent but severe condition occurring after Fontan procedure. The multifactorial pathogenesis remains unclear and no single proposed treatment strategy has proven universally successful. Therefore, we sought to describe different treatment strategies and their effect on clinical outcome and mortality.Material and Methods:We performed a retrospective observational study. From the total cohort of 439 Fontan patients treated in our institution during the study period 1986–2019, 30 patients (6.8%) with protein-losing enteropathy were identified. Perioperative, clinical, echocardiographic, laboratory, and invasive haemodynamic findings and treatment details were analysed.Results:Median follow-up after disease onset was 13.1 years [interquartile range 10.6]. Twenty-five patients received surgical or interventional treatment for haemodynamic restrictions. Medical treatment, predominantly pulmonary vasodilator and/or systemic anti-inflammatory therapy with budesonide, was initiated in 28 patients. In 15 patients, a stable remission could be achieved by medical or surgical procedures (n = 3 each), by combined multimodal therapy (n = 8), or ultimately by cardiac transplantation (n = 1). Phrenic palsy, bradyarrhythmia, Fontan pathway stenosis, and absence of a fenestration were significantly associated with development of protein-losing enteropathy (p = 0.001–0.48). Ten patients (33.3%) died during follow-up; 5-year survival estimate was 96.1%. In unadjusted analysis, medical therapy with budesonide and pulmonary vasodilator therapy in combination was associated with improved survival.Conclusions:Protein-losing enteropathy is a serious condition limiting survival after the Fontan procedure. Comprehensive assessment and individual treatment strategies are mandatory to achieve best possible outcome. Nevertheless, relapse is frequent and long-term mortality substantial. Cardiac transplantation should be considered early as treatment option.

Download Full-text