Reimagining AAV, the Ultimate Bioengineered
Delivery Vehicle

Adeno-associated viruses (AAVs) are non-pathogenic viruses that can be engineered to deliver DNA to drive the endogenous production of therapeutic proteins within specific target tissues. By programming cells to produce particular proteins, AAV gene therapies can convert transduced cells into local “biofactories” for these therapeutic proteins to achieve the desired clinical effect.

Advantages of AAV gene therapy
  • AAVs are non-pathogenic viruses that have been studied extensively in clinical settings, with substantial existing clinical safety experience
  • AAVs have been demonstrated to have lower immunogenicity compared to other viral vectors
  • AAVs have the potential to deliver durable, even lifelong clinical benefit following one-time administration (a “one-and-done” effect)
  • AAVs are suitable for direct-to-tissue delivery, enabling direct injection into the relevant site of pathology or desired biological activity

We believe in the potential of gene therapy to address a broad range of diseases. We view AAV as the ultimate delivery vehicle to drive the durable endogenous production of therapeutically relevant proteins, when rationally and deliberately engineered.

SIRVETM: our proprietary intelligent vector design platform

SIRVE (System for Intelligent Rational Vector Engineering) is our technology-enabled platform for de novo vector design, sequence modification, and data analysis. We marry computer science with the latest developments in vector biology to minimize immunogenicity, improve tissue specificity, and enhance the expression and manufacturability of our gene therapies. SIRVE is built for modularity, to enable the targeted focal production of desired therapeutic proteins using rationally engineered AAV vectors.

Reduced Immunogenicity

Minimizing the presence of immunostimulatory features through targeted sequence modification

Enhanced Expression

Selecting the optimal capsid for target tissue transduction, and engineering cassettes to achieve robust expression

SIRVE

Improved Tissue Specificity

Combining novel design elements with focal delivery techniques to achieve selective expression within the relevant tissue

Improved Manufacturability

Engineering the vectors to achieve maximal packaging efficiency while minimizing impurities within the final product

SIRVE

Reduced Immunogenicity

Minimizing the presence of immunostimulatory features through targeted sequence modification

Enhanced Expression

Selecting the optimal capsid for target tissue transduction, and engineering cassettes to achieve robust expression

Improved Tissue Specificity

Combining novel design elements with focal delivery techniques to achieve selective expression within the relevant tissue

Improved Manufacturability

Engineering the vectors to achieve maximal packaging efficiency while minimizing impurities within the final product

Optimizing the Expression Cassette

We take a methodical approach to de novo vector design and targeted sequence modification to engineer and optimize our therapeutic constructs.

the backbone is an element of the expression cassette that is necessary to manufacture the AAV, but does not serve a functional purpose in the therapeutic product. Nevertheless, a portion of the backbone often gets packaged into the AAV and is considered a contaminant in the final product. Deliberate engineering of the backbone with proprietary inert sequences can help reduce “reverse packaging” – the degree to which plasmid backbone DNA gets packaged into the AAV the Inverted Terminal Repeats (ITRs) demarcate the DNA sequence for packaging into the AAV. Maintaining consistency of the ITRs is critical throughout the production process. In addition, when possible, immunostimulatory regions should be removed the Polyadenylation (PolyA) signal is located at the end of the expression cassette and promotes the stability and longevity of the transcript. Many factors go into selecting the optimal PolyA sequence for a given expression cassette, with an additional goal of minimizing immunogenic responses the open reading frame (ORF) includes the transgene that encodes for the desired protein product. In engineering the ORF, it is important to minimize the presence of immunostimulatory motifs, utilize strong signaling and appropriate linker sequences, and avoid the creation of nonsense proteins the promoter is a regulatory element that drives expression of the transgene. Selection of the appropriate promoter is critical to achieving robust and durable expression in the desired tissue without triggering an immunostimulatory response the Inverted Terminal Repeats (ITRs) demarcate the DNA sequence for packaging into the AAV. Maintaining consistency of the ITRs is critical throughout the production process. In addition, when possible, immunostimulatory regions should be removed Include immunomodulatory or tissue-specific micro RNA sequences Include immunomodulatory or tissue-specific micro RNA sequences Include immunomodulatory or tissue-specific micro RNA sequences Include immunomodulatory or tissue-specific micro RNA sequences Include immunomodulatory or tissue-specific micro RNA sequences Include immunomodulatory or tissue-specific micro RNA sequences
Promoter

The promoter is a regulatory element that drives expression of the transgene. Selection of the appropriate promoter is critical to achieving robust and durable expression in the desired tissue.

Open Reading Frame

The open reading frame (ORF) includes the transgene that encodes for the desired protein product. In engineering the ORF, it is important to minimize the presence of immunostimulatory motifs, utilize strong and appropriate signaling elements, and ensure the generation of optimally folded and functionally active proteins.

PolyA

The Polyadenylation (PolyA) signal is located at the end of the expression cassette and promotes the stability and longevity of the transcript. 

ITR

The ITRs demarcate the DNA sequence and play a key role in its packaging into the AAV capsid particles. The ITRs also play a critical role in the formation of concatemers that ensure long term transgene expression following AAV delivery to human subjects. Maintaining consistency and integrity of the ITRs is critical throughout the production process.

Backbone

The backbone is a part of the plasmid DNA that is used in the production of AAV but does not serve a functional purpose in the final drug product. Nevertheless, portions of the backbone often get packaged into the final product and are considered impurities. Rational engineering of the backbone can help reduce the degree of plasmid backbone packaging and the potential immunogenicity associated with such impurities.

Our Pipeline

We focus on developing gene therapies for diseases with well-understood biology and established clinical endpoints, and where the durable expression of a particular therapeutic protein could have a transformative clinical impact. We select targets for which we anticipate a manageable total AAV dose is required to have the desired therapeutic effect. Our pipeline includes internally developed products as well as programs originated at leading academic institutions around the world.

KT-A112 - Type 1 Diabetes

Metabolic Disease

KT-A281 - Solid Tumors

Immuno-Oncology

KT-A252 - Geographic Atrophy

KT-A261 - Uveitis

Ophthalmology

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