Conventional Vectors

Conventional Vector Approaches to Gene Therapy Face Four Fundamental Challenges:

1.
Lack of efficient delivery to specific tissues and/or cell types due to physical barriers

Conventional naturally-occurring AAVs have not been designed or engineered to circumvent natural barriers to viral vector delivery, such as clearance by the liver or the inner-limiting membrane of the retina, and they are not targeted to specific tissues or cells. As a result, products using these vectors may require suboptimal delivery mechanisms or high doses to achieve therapeutic benefit.

2.
Lack of efficient transduction of specific target cell types

To yield therapeutic benefit, the vector must efficiently deliver its transgene from the cell surface into the target cell nucleus, resulting in subsequent therapeutic transgene expression within the cell. Conventional AAVs are not designed or engineered for efficient transduction of specific target cells. As a consequence, conventional vectors may be associated with inefficient transduction and transgene expression which would limit efficacy.

3.
Potential to cause toxicity due to inflammation

Conventional AAV vector based products have been associated with inflammation-related toxicities in some patients. Potential contributing factors may include the lack of specificity with current conventional AAV vectors, the high intravenous doses required for delivery to target tissues, and the ability of these AAVs to transduce immune cells.

4.
Neutralization by pre-existing antibodies

The human immune system has evolved to fight viruses, including conventional AAVs that are present in nature. Widespread exposure to these conventional AAVs has resulted in neutralizing antibodies in a large portion of the population (approximately 30% to 70% depending on the vector serotype and patient population); these antibodies can limit gene delivery and the addressable patient population with conventional vectors. In addition, re-dosing with the same vector is generally not feasible given the induction of neutralizing antibodies to the vector.

While gene therapy holds tremendous promise as a transformative therapeutic class, the majority of gene therapeutic approaches utilize naturally-occurring or conventional adeno-associated virus (AAV) vectors that have encountered limitations such as high dose requirements, limited efficacy, inflammation and toxicity, and neutralization by pre-existing antibodies. As a result of these shortcomings, current efforts with conventional AAV vectors have focused on diseases in which a surgical technique is used for direct cell access such as subretinal injection for the retina, or a low level of gene expression may be sufficient for patient benefit, such as Hemophilia A or B treatment.

Rather than using conventional AAV vectors for our products, we instead take a “disease first” approach by creating proprietary customized AAV vectors for each disease through our Therapeutic Vector Evolution platform.