Retraction Note: Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies
Related Articles
Preclinical assessment of a ganglioside-targeted therapy for Parkinson’s disease with the first-in-class adaptive peptide AmyP53
We propose a new concept for the treatment of Parkinson’s disease (PD), which considers that its root cause, α-synuclein, is an intrinsically disordered protein (IDP) difficult to target by classic approaches. Upon binding to lipid raft gangliosides, α-synuclein shifts from random coil to α-helix, forming Ca2+-permeable oligomeric pores triggering a neurotoxicity cascade. We used the α-synuclein-ganglioside interaction as guideline to design a therapeutic peptide (AmyP53) that combines the respective flexible ganglioside-binding domains of α-synuclein and Alzheimer’s β-amyloid protein. AmyP53 is an adaptive peptide, the first representant of a new therapeutic class. It acts as a competitive inhibitor of α-synuclein oligomer formation in brain cell membranes and prevents subsequent downstream synaptotoxicity, including the loss of dopaminergic neurons in an animal α-synuclein injection model of PD. It is active against both wild-type and mutant forms of α-synuclein. AmyP53 is administered intranasally without side effects. This new concept “target the target (gangliosides), not the arrow (IDP)” is distinct from classic α-synuclein centric approaches that did not cure PD so far.
Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines
The successful approval of peptide-based drugs can be attributed to a collaborative effort across multiple disciplines. The integration of novel drug design and synthesis techniques, display library technology, delivery systems, bioengineering advancements, and artificial intelligence have significantly expedited the development of groundbreaking peptide-based drugs, effectively addressing the obstacles associated with their character, such as the rapid clearance and degradation, necessitating subcutaneous injection leading to increasing patient discomfort, and ultimately advancing translational research efforts. Peptides are presently employed in the management and diagnosis of a diverse array of medical conditions, such as diabetes mellitus, weight loss, oncology, and rare diseases, and are additionally garnering interest in facilitating targeted drug delivery platforms and the advancement of peptide-based vaccines. This paper provides an overview of the present market and clinical trial progress of peptide-based therapeutics, delivery platforms, and vaccines. It examines the key areas of research in peptide-based drug development through a literature analysis and emphasizes the structural modification principles of peptide-based drugs, as well as the recent advancements in screening, design, and delivery technologies. The accelerated advancement in the development of novel peptide-based therapeutics, including peptide-drug complexes, new peptide-based vaccines, and innovative peptide-based diagnostic reagents, has the potential to promote the era of precise customization of disease therapeutic schedule.
Prasinezumab slows motor progression in Parkinsons disease: beyond the clinical data
A post hoc subgroup analysis has suggested potential therapeutic benefits of prasinezumab, a humanized monoclonal anti-α-synuclein antibody, in patients with rapidly progressing Parkinson’s disease (PD), despite initial trials showing limited impact on primary outcomes. Caution is needed due to the retrospective nature of subgroup analyses, and potential confounding factors that may have influenced the observed treatment effects in specific patient subsets. Critical considerations are provided here for designing and implementing preclinical studies and clinical trials involving monoclonal antibodies, suggesting that future research should prioritize refining preclinical models and optimizing biomarker-based patient selection to reduce risks of false trial outcomes, eventually advancing antibody-based therapies in PD effectively and safely.
Optimizing rabies mRNA vaccine efficacy via RABV-G structural domain screening and heterologous prime-boost immunization
mRNA vaccine has become a promising technology platform for rabies prevention. This study explores the roles of different structural domains of rabies virus glycoprotein (RABV-G) and heterologous prime-boost strategies for enhanced immune responses and protection. The results suggested that mRNA vaccines encoding full-length RABV-G (RABV-Full) and RABV-R333Q induced strong immune responses and provided full protection against rabies, while mRNA vaccines encoding ectodomain/transmembrane domain (RABV-TE) and ectodomain (RABV-E) were less effective. Heterologous immunization results revealed that mRNA-primed strategies yielded higher long-lasting VNTs, but lower early VNTs than inactivated rabies virus (IRV)-primed strategies. 2×RABV-Full and IRV > RABV-Full provided 100% protection, while that of RABV-Full>IRV was 90%. Transcriptome analysis showed that rabies mRNA vaccine induced both MHCI and MHCII antigen presentation, as well as B/T cell activation. In conclusion, full-length RABV-G mRNA vaccines, particularly with an ‘IRV prime and RABV-Full boost’ strategy, hold great potential for rabies prevention.
Recent advances and perspectives on the development of circular RNA cancer vaccines
Engineered circular RNAs (circRNAs) are emerging as promising platforms for RNA-based vaccines in cancer treatment. We summarize the recent advances of design, synthesis, and delivery of circRNA-based cancer vaccines, and highlight the applications and challenges of circRNA vaccines in cancer therapy. Further enhancements are required in areas such as antigen selection, targeted delivery, multidimensional crosstalks, and clinical trial assessments to advance the efficacy and safety of circRNA vaccines in cancer.
Responses