bims-curels 2022-11-27 papers

Issue of 2022–11–27
seven papers selected by
Cure Mito Foundation

Int Rev Neurobiol. 2022 ;pii: S0074-7742(22)00098-8. [Epub ahead of print]166 281-312

More than a participant in trials of cell and gene therapy: Hearing the voices of people living with neurodegenerative diseases.

Emma L Lane, Lyndsey Isaacs, Soania Mathur.

With the advent of novel advanced therapy medicinal products (ATMPs) for neurodegenerative diseases, their pathway to clinical trials and the therapeutic landscape has highlighted some new challenges, many of which are outlined in other chapters of this volume. The practical considerations of all these aspects from basic research and animal models through to clinical trials and eventual clinical implementation are significant. By and large, the major voices surrounding these challenges are the scientists and clinical teams who both develop the interventions and design and deliver the clinical trials to test these novel ATMPs. Their expertise is of course essential, but there is a key voice that can add considerable benefit to the pipeline, that of the lived experience of the disease being treated and the new intervention being considered. While still in their relative infancy in neurodegenerative disease, some ATMPs are already in clinical application in other disease areas, mainly cancer and inherited disorders. This more advanced status has raised some interesting questions about the role of the patient voice across all aspects of the therapeutic research and clinical delivery pipeline. This chapter highlights what has been learnt from the patient voice in their understanding and perspectives of ATMPs and in their experiences of clinical trials in neurodegenerative diseases to date. We discuss when, and how, including people living with neurodegenerative disease is of value in the development and implementation of ATMPs and the questions this collaborative effort can allow us to answer.

Keywords: ATMP; Diversity; PPIE; Participant; Public and patient involvement

DOI: https://doi.org/10.1016/bs.irn.2022.09.007

Int Rev Neurobiol. 2022 ;pii: S0074-7742(22)00097-6. [Epub ahead of print]166 235-279

Considerations for clinical trial design and conduct in the evaluation of novel advanced therapeutics in neurodegenerative disease.

Cheney J G Drew, Monica Busse.

The recent advances in the development of potentially disease modifying cell and gene therapies for neurodegenerative disease has resulted in the production of a number of promising novel therapies which are now moving forward to clinical evaluation. The robust evaluation of these therapies pose a significant number of challenges when compared to more traditional evaluations of pharmacotherapy, which is the current mainstay of neurodegenerative disease symptom management. Indeed, there is an inherent complexity in the design and conduct of these trials at multiple levels. Here we discuss specific aspects requiring consideration in the context of investigating novel cell and gene therapies for neurodegenerative disease. This extends to overarching trial designs that could be employed and the factors that underpin design choices such outcome assessments, participant selection and methods for delivery of cell and gene therapies. We explore methods of data collection that may improve efficiency in trials of cell and gene therapy to maximize data sharing and collaboration. Lastly, we explore some of the additional context beyond efficacy evaluations that should be considered to ensure implementation across relevant healthcare settings.

Keywords: Disease registries; Intra-cranial delivery; Participant selection; Trial design

DOI: https://doi.org/10.1016/bs.irn.2022.09.006

J Appl Physiol (1985). 2022 Nov 23.

The role of exerkines on brain mitochondria: a mini-review.

Junwon Heo, Emily E Noble, Jarrod A Call.

Exercise benefits many organ systems, including having a panacea-like effect on the brain. For example, aerobic exercise improves cognition and attention and reduces the risk of brain-related diseases, such as dementia, stress, and depression. Recent advances suggest that endocrine signaling from peripheral systems, such as skeletal muscle, mediates the effects of exercise on the brain. Consequently, it has been proposed that factors secreted by all organs in response to physical exercise should be more broadly termed the "exerkines". Accumulating findings suggest that exerkines derived from skeletal muscle, liver, and adipose tissues directly impact brain mitochondrial function. Mitochondria play a pivotal role in regulating neuronal energy metabolism, neurotransmission, cell repair, and maintenance in the brain, and therefore exerkines may act via impacting brain mitochondria to improve brain function and disease resistance. Therefore, herein we review studies investigating the impact of muscle-, liver-, and adipose tissue-derived exerkines on brain cognitive and metabolic function via modulating mitochondrial bioenergetics, content, and dynamics under healthy and/or disease conditions.

Keywords: Adipokines; Exercise; Hepatokines; Mitochondria; Myokines

DOI: https://doi.org/10.1152/japplphysiol.00565.2022

Surg Oncol Clin N Am. 2023 Jan;pii: S1055-3207(22)00067-9. [Epub ahead of print]32(1): 221-232

Diversity, Equity, and Inclusion in Clinical Trials.

Grace Keegan, Angelena Crown, Kathie-Ann Joseph.

Minority groups are vastly underrepresented in clinical trial participants and leadership. Because these studies provide innovative and revolutionary treatment options to patients with cancer and have the potential to extend survival, it is imperative that public and private stakeholders, as well as hospital and clinical trial leadership, prioritize equity and inclusion of diverse populations in clinical trial development and recruitment strategies. Achieving equity in clinical trials could be an important step in reducing the overall cancer burden and mortality disparities in vulnerable populations.

Keywords: Clinical trials; Diversity; Equity; Inclusion; Minority groups; Vulnerable populations

DOI: https://doi.org/10.1016/j.soc.2022.08.005

Front Pharmacol. 2022 ;13 1011740

Natural product-based pharmacological studies for neurological disorders.

Vivek Puri, Neha Kanojia, Ameya Sharma, Kampanart Huanbutta, Divya Dheer, Tanikan Sangnim.

Central nervous system (CNS) disorders and diseases are expected to rise sharply in the coming years, partly because of the world's aging population. Medicines for the treatment of the CNS have not been successfully made. Inadequate knowledge about the brain, pharmacokinetic and dynamic errors in preclinical studies, challenges with clinical trial design, complexity and variety of human brain illnesses, and variations in species are some potential scenarios. Neurodegenerative diseases (NDDs) are multifaceted and lack identifiable etiological components, and the drugs developed to treat them did not meet the requirements of those who anticipated treatments. Therefore, there is a great demand for safe and effective natural therapeutic adjuvants. For the treatment of NDDs and other memory-related problems, many herbal and natural items have been used in the Ayurvedic medical system. Anxiety, depression, Parkinson's, and Alzheimer's diseases (AD), as well as a plethora of other neuropsychiatric disorders, may benefit from the use of plant and food-derived chemicals that have antidepressant or antiepileptic properties. We have summarized the present level of knowledge about natural products based on topological evidence, bioinformatics analysis, and translational research in this review. We have also highlighted some clinical research or investigation that will help us select natural products for the treatment of neurological conditions. In the present review, we have explored the potential efficacy of phytoconstituents against neurological diseases. Various evidence-based studies and extensive recent investigations have been included, which will help pharmacologists reduce the progression of neuronal disease.

Keywords: bioinformatic tools; clinical research; natural products; neurological disorders; translational research

DOI: https://doi.org/10.3389/fphar.2022.1011740

Elife. 2022 Nov 21. pii: e65488. [Epub ahead of print]11

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (1), including the lrpprc locus. Here we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Keywords: developmental biology; genetics; genomics; zebrafish

DOI: https://doi.org/10.7554/eLife.65488

Comput Struct Biotechnol J. 2022 ;20 6388-6402

Mitochondrial RNA editing in Trypanoplasma borreli: New tools, new revelations.

Evgeny S Gerasimov, Dmitry A Afonin, Oksana A Korzhavina, Julius Lukeš, Ross Low, Neil Hall, Kevin Tyler, Vyacheslav Yurchenko, Sara L Zimmer.

The kinetoplastids are unicellular flagellates that derive their name from the 'kinetoplast', a region within their single mitochondrion harboring its organellar genome of high DNA content, called kinetoplast (k) DNA. Some protein products of this mitochondrial genome are encoded as cryptogenes; their transcripts require editing to generate an open reading frame. This happens through RNA editing, whereby small regulatory guide (g)RNAs direct the proper insertion and deletion of one or more uridines at each editing site within specific transcript regions. An accurate perspective of the kDNA expansion and evolution of their unique uridine insertion/deletion editing across kinetoplastids has been difficult to achieve. Here, we resolved the kDNA structure and editing patterns in the early-branching kinetoplastid Trypanoplasma borreli and compare them with those of the well-studied trypanosomatids. We find that its kDNA consists of circular molecules of about 42 kb that harbor the rRNA and protein-coding genes, and 17 different contigs of approximately 70 kb carrying an average of 23 putative gRNA loci per contig. These contigs may be linear molecules, as they contain repetitive termini. Our analysis uncovered a putative gRNA population with unique length and sequence parameters that is massive relative to the editing needs of this parasite. We validated or determined the sequence identity of four edited mRNAs, including one coding for ATP synthase 6 that was previously thought to be missing. We utilized computational methods to show that the T. borreli transcriptome includes a substantial number of transcripts with inconsistent editing patterns, apparently products of non-canonical editing. This species utilizes the most extensive uridine deletion compared to other studied kinetoplastids to enforce amino acid conservation of cryptogene products, although insertions still remain more frequent. Finally, in three tested mitochondrial transcriptomes of kinetoplastids, uridine deletions are more common in the raw mitochondrial reads than aligned to the fully edited, translationally competent mRNAs. We conclude that the organization of kDNA across known kinetoplastids represents variations on partitioned coding and repetitive regions of circular molecules encoding mRNAs and rRNAs, while gRNA loci are positioned on a highly unstable population of molecules that differ in relative abundance across strains. Likewise, while all kinetoplastids possess conserved machinery performing RNA editing of the uridine insertion/deletion type, its output parameters are species-specific.

Keywords: ATPase 6; Euglenozoa; Maxicircle; Metakinetoplastina; Mitochondrion; RNA editing; U-indel editing, Uridine insertion/deletion editing; guide RNA

DOI: https://doi.org/10.1016/j.csbj.2022.11.023