====== Adenoviral therapy ======
Refers to the use of genetically modified adenoviruses—a type of DNA virus—as tools for treating diseases, particularly cancer. Here's a quick overview adapted to both general understanding and clinical research relevance:

🔬 Definition
Adenoviral therapy is a form of gene therapy or oncolytic virotherapy where adenoviruses are engineered to either:

Deliver therapeutic genes into target cells (e.g., p53 tumor suppressor),

Selectively replicate in and kill cancer cells (oncolytic adenoviruses),

Or stimulate an anti-tumor immune response.

⚙️ Mechanism of Action
Infects host cell via specific receptors (e.g., CAR receptor).

Delivers DNA payload into the nucleus (non-integrating).

Gene expression or viral replication occurs based on design.

Cell lysis (in oncolytic versions) releases tumor antigens → promotes immune response.

🧪 Applications
Cancer (Oncolytic virotherapy): Glioblastoma, pancreatic cancer, prostate cancer, etc.

Gene delivery: Cystic fibrosis, cardiovascular disease, vaccines (e.g. COVID-19 vaccines like AstraZeneca use chimpanzee adenovirus).

Immunotherapy adjunct: Boosts immune system via danger signals and antigen presentation.

🚧 Challenges
Systemic delivery: Rapid clearance by the immune system and liver uptake.

Pre-existing immunity: Many people have neutralizing antibodies against common human adenoviruses.

Toxicity and inflammation: Especially in high-dose systemic therapy.

Targeting specificity: Tumor-selective replication or gene expression is hard to control.

Repeat dosing: Often limited due to immune memory.

🧬 Next-Generation Approaches
Use of non-human adenovirus serotypes (e.g., chimpanzee Ad vectors).

Retargeted capsid modifications for tumor-specific tropism.

Armed oncolytic viruses with immunostimulatory transgenes (e.g., GM-CSF).

Shielding strategies like PEGylation or use of extracellular vesicles.

Combos with checkpoint inhibitors or chemotherapy.

====== Engineered retargeting to overcome systemic delivery challenges in oncolytic adenoviral therapy ======

**Type of study:** Original research ([[experimental study]], engineering approach)  
**First author:** Leparc et al.  
**Affiliations:**  
  * Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, [[Boston]], MA, USA  
  * Laboratory of Nervous System Disorders and Therapy, GIGA Institute, University of Liège, Liège, Belgium  
**Journal:** Molecular Therapy – Oncolytics  
**Purpose:**  
To engineer [[adenovirus]]es with modified [[tropism]] for systemic delivery—aiming to reduce off-target accumulation and enhance tumor retention via retargeting strategies.

**Conclusions:**  
Engineered vectors exhibited improved [[immune evasion]], diminished sequestration by non-tumor tissues, and improved intratumoral delivery, indicating the feasibility of retargeting modifications for systemic [[adenoviral therapy]].

===== Critical Review =====

**Methodology:**  
The study lacks [[transparency]] in the engineering protocol. Crucial elements such as ligand selection, targeting affinity, and vector modifications are insufficiently described. No rigorous dose-responsiveness or replication kinetics are provided.

**Experimental Limitations:**  
Only limited xenograft models were used. The absence of immunocompetent or metastatic models weakens any extrapolation to clinical practice.

**Immunological Oversight:**  
There is no data on host immune responses or neutralizing antibody development over time. This omission is critical for systemically delivered viral therapies.

**Safety and Toxicology:**  
Claims of reduced off-target effects are unsupported by comprehensive toxicity or biodistribution data. Lack of liver, lung, or spleen histopathology undermines safety assertions.

**Comparative Context:**  
The study fails to [[benchmark]] against existing retargeting approaches like bispecific adaptors or nanoparticle-based carriers, weakening claims of novelty or superiority.

**Data Accessibility:**  
Raw data including viral load, distribution curves, and replication efficiency are omitted. Figures are descriptive but lack statistical rigor.

===== Final Verdict =====

While conceptually relevant, this study lacks empirical robustness and critical comparative analysis. Its translational impact is unsubstantiated due to poor methodological and immunological validation.

===== Takeaway for Neurosurgeons =====

Systemic delivery of engineered oncolytic adenoviruses is promising, but this study’s incomplete immunological and toxicological evaluation renders it clinically unconvincing for neuro-oncology application.

===== Bottom Line =====

High-concept, low-rigor: currently inadequate for informing clinical or translational strategies.

===== Rating =====

**2 / 10**

===== Citation =====

Leparc L, Wakimoto H. *Engineered retargeting to overcome systemic delivery challenges in oncolytic adenoviral therapy*. Mol Ther Oncolytics. 2025 Jun 6;33(2):201005. doi:10.1016/j.omton.2025.201005.  

**Full title:** Engineered retargeting to overcome systemic delivery challenges in oncolytic adenoviral therapy  
**Publication date:** June 6, 2025  
**Corresponding author email:** Not publicly available