AAV Atlas Overview

AAV-Atlas is a cutting-edge bioinformatics resource built on the GLUE platform, tailored for genomic analysis of adeno-associated viruses (AAVs). The project addresses the growing need for a robust, standardized framework to manage, analyze, and share AAV sequence data in light of their critical role in gene therapy development. AAV-Atlas combines genomic data integration, rich metadata annotation, and advanced analysis capabilities.

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Background and Motivation

Recombinant AAV (rAAV) therapies have emerged as safe and effective treatments for a variety of monogenic and acquired diseases, particularly those lacking alternative options. With the increasing approval rates of rAAV-based therapies and anticipated submissions for new drug applications, the importance of addressing challenges like tissue tropism, immune evasion, packaging capacity, and toxicity has grown. Many of these challenges can be mitigated through genomic analysis of AAV data.

However, effective genomic analysis requires a system capable of handling inconsistent annotations, mislabeling, and uneven genome coverage. AAV-Atlas was developed to overcome these obstacles by providing a comprehensive and flexible platform for managing AAV sequence data and facilitating comparative genomics.

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Key Features

1. Comprehensive AAV Genomic Resources:

   • Annotated Reference Sequences: Curated from diverse AAV species and serotypes, providing a complete view of genomic diversity.
   • Genome Feature Definitions: Includes both coding and non-coding features, enabling detailed annotation and comparative studies.
   • Phylogenetic Genotyping Algorithm: Facilitates clade-specific classification and analysis.

2. Mutation and Variant Analysis:

   • Detailed tracking of amino acid replacements and their frequencies across datasets.
   • Standardized mutation definitions supporting functional and regulatory studies.

3. Alignment and Phylogenetics:

   • Structured alignment trees and constrained MSAs to ensure robust evolutionary analysis.
   • Integrated phylogenies prepared and validated for accurate lineage mapping.

4. Data Integration:

   • Rich metadata capturing collection details, host species, and geographic origins.
   • Automated GenBank data extraction ensures consistency and thorough coverage.

5. Custom Extensions for Nuccore Data:

   • Additional sequence data from NCBI Nuccore enhances dataset diversity.
   • Species- and patent-level annotations enrich the contextual understanding of sequences.

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Applications

1. Research and Development of rAAV Therapies

• Vector Design: Identify AAV strains with favorable properties for gene therapy, such as tissue-specific tropism and immune evasion.
• Capsid Engineering: Study the impact of genetic variations on capsid properties to optimize transduction efficiency and reduce immune responses.

2. Clinical Applications

• Patient-Specific Therapies: Design personalized AAV vectors based on immune profiles and pre-existing antibodies.
• Treatment Prediction: Correlate AAV genotypes and mutations with clinical outcomes to anticipate efficacy and safety.

3. Evolutionary and Functional Genomics

• Study evolutionary relationships and pressures shaping AAV diversity.
• Investigate the functional consequences of specific mutations on viral properties like capsid stability and receptor binding.

4. Standardization and Regulatory Support

• Standardized mutation and genotype definitions streamline regulatory submissions.
• Quality control ensures consistency in AAV vector production.

5. Data Integration and Public Health

• Track the prevalence and spread of AAV strains.
• Facilitate collaboration among researchers, clinicians, and industry partners.

6. Therapeutic Monitoring

• Monitor genetic changes in AAV vectors post-therapy.
• Support long-term follow-up studies on treated patients.

7. Educational and Diagnostic Tools

• Train students and professionals in virology and gene therapy.
• Develop diagnostic assays for detecting AAV genotypes and mutations.

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Practical Use Case: Enhancing rAAV Therapeutic Design

AAV-Atlas enables a structured approach to identify and optimize AAV strains for gene therapy:

1. Query database for tissue-specific tropism or immune evasion properties.
2. Experimentally validate identified strains in relevant biological systems.
3. Engineer capsid variants with improved therapeutic properties, informed by mutation analysis.
4. Use high-throughput screening and genotype-phenotype mapping to refine candidates.
5. Integrate findings into the database, supporting iterative improvements.

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Collaborative Potential for BioTech Companies

Biotech organizations can leverage AAV-Atlas for:

• High-throughput screening and library creation.
• Genotype-phenotype correlation using machine learning models.
• Structural analysis to predict the impact of mutations.
• Data sharing within consortia and regulatory compliance.

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