The Latest Articles on Targeted Therapy for Neurodegenerative Diseases

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on Targeted Therapy for Neurodegenerative Diseases.

Title: Anti-tau intrabodies: From anti-tau immunoglobulins to the development of functional scFv-intrabodies
Authors: Dina Rodrigues Martins, Fern Sha, Wim Van der Elst, Pei-Yu Shih, Jens Devoght, Kristof Van Kolen, Marc Mercken, Bianca Van Broeck, Paul Declerck, Clara Theunis
Type: Research Article

Abstract:

Over the last decade, there has been a growing interest in intrabodies and their therapeutic potential. Intrabodies are antibody fragments that are expressed inside a cell to target intracellular antigens. In the context of intracellular protein misfolding and aggregation, such as tau pathology in Alzheimer’s disease, intrabodies have become an interesting approach as there is the possibility to target early stages of aggregation. As such, we engineered three anti-tau monoclonal antibodies into single-chain variable fragments for cytoplasmic expression and activity: PT51, PT77 and hTau21. Due to the reducing environment of the cytoplasm, single-chain variable fragment (scFv) aggregation is commonly observed. Therefore, we also performed complementarity-determining region (CDR) grafting into three different stable frameworks to rescue solubility and intracellular binding. All three scFvs retained binding to tau after cytoplasmic expression in HEK293 cells, in at least one of the frameworks. Subsequently, we show their capacity to interfere with either mouse or mutant human tau aggregation in two different primary mouse neuron models and organotypic hippocampal slice cultures. Collectively, our work extends the current knowledge on intracellular tau targeting with intrabodies, providing three scFv-intrabodies that can be used as immunological tools to target tau inside cells.

Access this article: https://doi.org/10.1016/j.omtm.2023.101158

Title: Neuronanomedicine for Alzheimer’s and Parkinson’s disease: Current progress and a guide to improve clinical translation
Authors: India Boyton, Stella M. Valenzuela, Lyndsey E. Collins-Praino, Andrew
Type: Research Article

Abstract:

Neuronanomedicine is an emerging multidisciplinary field that aims to create innovative nanotechnologies to treat major neurodegenerative disorders, such as Alzheimer’s (AD) and Parkinson’s disease (PD). A key component of neuronanomedicine are nanoparticles, which can improve drug properties and demonstrate enhanced safety and delivery across the blood brain barrier, a major improvement on existing therapeutic approaches. In this review, we critically analyze the latest nanoparticle-based strategies to modify underlying disease pathology to slow or halt AD/PD progression. We find that a major roadblock for neuronanomedicine translation to date is a poor understanding of how nanoparticles interact with biological systems (i.e., bio-nano interactions), which is partly due to inconsistent reporting in published works. Accordingly, this review makes a set of specific recommendations to help guide researchers to harness the unique properties of nanoparticles and thus realise breakthrough treatments for AD/PD.

Access this article: https://doi.org/10.1016/j.bbi.2023.11.004

Title: Genomic and transcriptomic advances in amyotrophic lateral sclerosis
Authors: Mafalda Rizzuti, Luca Sali, Valentina Melzi, Simone Scarcella, Gianluca Costamagna, Linda Ottoboni, Lorenzo Quetti, Lorenzo Brambilla, Dimitra Papadimitriou, Federico Verde, Antonia Ratti, Nicola Ticozzi, Giacomo Pietro Comi, Stefania Corti, Delia Gagliardi
Type: Review
Abstract:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.

Access this article: https://doi.org/10.1016/j.arr.2023.102126

Title: Omaveloxolone ameliorates cognitive dysfunction in APP/PS1 mice by stabilizing the STAT3 pathway
Authors: Xiaolin Cui, Shuai Zong, Wenao Song, Cuicui Wang, Yingchao Liu, Li Zhang, Pengcheng Xia, Xueying Wang, Hao Zhao, Le Wang, Zhiming Lu
Type: Research Article
Abstract:

Aims
To determine the availability and the potential molecular mechanisms underlying the therapeutic effect of omaveloxolone (RTA408) on Alzheimer's Disease (AD).

Materials and methods
This study employed network pharmacology to assess the feasibility of drug treatment of AD. To determine the cognitive status and emotional state of APPswe/PS1dE9 (APP/PS1) mice after the RTA408 treatment, three classical behavioral experiments (water maze, Y-maze, and open field test) were conducted. Immunofluorescence and immunohistochemical staining were utilized to evaluate hippocampal neuronal status and amyloid (Aβ) deposition in mice. RNA-seq and transcription factor prediction analyses were performed to explore the potential molecular mechanisms regulating the therapeutic effects of RTA408. Molecular docking was employed to predict the direct drug targets. To validate these molecular mechanisms, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and immunofluorescence analyses were performed in two instrumental cell lines, i.e., mouse hippocampal neuronal cells (HT22) and microglia (BV2).

Results
RTA408 was revealed with the capability to reduce Aβ plaque deposition and to restore damaged neurons in the hippocampal region of APP/PS1 mice, ultimately leading to an improvement in cognitive function. This beneficial effect was achieved by balancing the STAT3 pathway. Specifically, RTA408 facilitated the activations of both STAT3/OXR1 and NRF2/ARE axes, thereby enhancing the compromised resistance in neurons to oxidative stress. RTA408 inhibited the NFκB/IL6/STAT3 pathway, effectively countering the neuroinflammation triggered by microglial activation.

Conclusion
RTA408 is revealed with promising potential in the treatment of AD based on preclinical data.
Access this article: https://doi.org/10.1016/j.lfs.2023.122261

Title: Catalyzing a Cure: Discovery and development of LRRK2 Inhibitors for the treatment of Parkinson’s disease
Authors: Anurag TK Baidya, Sonam Deshwal, Bhanuranjan Das, Alen T Mathew, Bharti Devi, Rajat Sandhir, Rajnish Kumar
Type: Review
Abstract:

Parkinson’s disease (PD) is an age-related second most common progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no effective disease modifying therapeutics have reached clinics for treatment/management of PD. Leucine-rich repeat kinase 2 (LRRK2) which controls membrane trafficking and lysosomal function and its variant LRRK2-G2019S are involved in the development of both familial and sporadic PD. LRRK2, is therefore considered as a legitimate target for the development of therapeutics against PD. During the last decade, efforts have been made to develop effective, safe and selective LRRK2 inhibitors and also our understanding about LRRK2 has progressed. However, there is an urge to learn from the previously designed and reported LRRK2 inhibitors in order to effectively approach designing of new LRRK2 inhibitors. In this review, we have aimed to cover the pre-clinical studies undertaken to develop small molecule LRRK2 inhibitors by screening the patents and other available literature in the last decade. We have highlighted LRRK2 as targets in the progress of PD and subsequently covered detailed design, synthesis and development of diverse scaffolds as LRRK2 inhibitors. Moreover, LRRK2 inhibitors under clinical development has also been discussed. LRRK2 inhibitors seem to be potential targets for future therapeutic interventions in the treatment and management of PD and this review can act as a cynosure for guiding discovery, design, and development of selective and non-toxic LRRK2 inhibitors. Although, there might be challenges in developing effective LRKK2 inhibitors, the opportunity to successfully develop novel therapeutics targeting LRKK2 against PD has never been greater.

Access this article: https://doi.org/10.1016/j.bioorg.2023.106972