Overcoming immunological challenges limiting capsid-mediated gene therapy with machine learning
A key hurdle to making adeno-associated virus (AAV) capsid mediated gene therapy broadly beneficial to all patients is overcoming pre-existing and therapy-induced immune responses to these vectors. Recent advances in high-throughput DNA synthesis, multiplexing and sequencing technologies …
Generative AAV capsid diversification by latent interpolation
Adeno-associated virus (AAV) capsids have shown clinical promise as delivery vectors for gene therapy. However, the high prevalence of pre-existing immunity against natural capsids poses a challenge for widespread treatment. The generation of diverse capsids that are …
Deep diversification of an AAV capsid protein by machine learning
Modern experimental technologies can assay large numbers of biological sequences, but engineered protein libraries rarely exceed the sequence diversity of natural protein families. Machine learning (ML) models trained directly on experimental data without biophysical modeling provide one route …
AdaLead: A simple and robust adaptive greedy search algorithm for sequence design
Efficient design of biological sequences will have a great impact across many industrial and healthcare domains. However, discovering improved sequences requires solving a difficult optimization problem. Traditionally, this challenge was approached by biologists through a model-free method known as “directed evolution” …
A primer on model-guided exploration of fitness landscapes for biological sequence design
Machine learning methods are increasingly employed to address challenges faced by biologists. One area that will greatly benefit from this cross-pollination is the problem of biological sequence design, which has massive potential for therapeutic applications. However, significant inefficiencies …
Accurately quantifying transduction within barcoded AAV capsid libraries via tracking of single-molecule ID tags
Multiplexed barcoded capsid libraries have emerged as a powerful tool for high-throughput AAV engineering. Barcoded studies facilitate the accurate measurement of tropism across multiple capsids within a single animal, which is essential to understanding why certain capsids better transduce key delivery targets …
Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design
Adeno-associated virus (AAV) capsids can deliver transformative gene therapies, but our understanding of AAV biology remains incomplete. We generated the complete first-order AAV2 capsid fitness landscape, characterizing all single-codon substitutions, insertions, and deletions across multiple functions…
Challenges and opportunities of machine-guided capsid engineering for gene therapy
Advances in DNA delivery will be crucial to the enablement of new gene therapies. Pioneering efforts in developing recombinant AdenoAssociated Virus (AAV) technology for gene delivery have led to a recent wave of treatments for genetic diseases with great unmet need. Most current therapies…