Therapeutic Vector Evolution

Therapeutic Vector Evolution is a discovery platform that empowers 4DMT to create optimized and proprietary AAV vectors, each specifically tailored for the treatment of patients with specific rare diseases with high unmet medical need. 4DMT vectors are designed and created following disease-specific “4DMT Target Vector Profiles”.

These optimized & proprietary “biopharmaceutical grade” AAV vectors are designed to allow us uniquely to unlock the full potential of gene therapy.

While AAV gene therapy pioneers are making great strides with the first wave of products, hurdles still exist with the use of 1st and 2nd generation vectors (naturally occurring primitive viral capsids). The most commonly used AAV capsids (e.g. AAV2, 5, 8 and 9) were identified either 1) as contaminants in lab stocks of adenovirus, or 2) through monkey tissue processing. Therefore, these primitive capsids are not targeted specifically to any tissue in the body. This can lead to inefficient and non-targeted delivery, thus requiring extremely high doses and potentially resulting in toxicities, problematic manufacturing burdens and suboptimal efficacy. In addition, suboptimal routes of delivery can be required for delivery to the right tissues (e.g. subretinal delivery in the retina). Finally, pre-existing neutralizing antibodies in patients can limit efficacy and enrollment. Innovation is required to create new and improved AAV capsids to allow targeted delivery by the optimal route of administration.

 

With the 4DMT vector discovery platform “Therapeutic Vector Evolution”, we use the power of evolution to create and then refine these optimized vectors to fit our 4DMT Target Vector Profile as follows:

STEP 1 – DESIGN THE TARGET VECTOR PROFILE: We work with physicians and scientists to design the best possible vector for a given disease. The Target Vector Profile will define the cell types and distribution within an organ to be targeted, the route of administration, the dosage required for delivery, and if desirable the resistance to pre-existing antibodies in the population.

STEP 2 – GENETIC DIVERSIFICATION: We create highly complex and unique vector capsid “libraries” for high-throughput screening. To date we have created over 30 unique capsid libraries comprising an estimated 100 million novel variants. We therefore have roughly 10 million times more vectors to choose from than the lead products in the field.

STEP 3 – NATURAL SELECTION IN VIVO: We use the power of natural selection to isolate the “most fit” vectors for any “Target Vector Profile” we design (see above).

Once we have created and discovered these highly optimized 4DMT AAV vectors, we then can engineer them to carry a wide array of therapeutic transgenes for different disease-targeting products, in addition to filing composition-of-matter patents and use patents.

Overcoming the limitations with 1st and 2nd generation, naturally occurring & primitive AAV vectors: How can 4DMT optimized vectors help to overcome the limitations shown with other AAV vectors? The following is a list of 4DMT target vector features:

 

Highly efficient gene uptake:
Our vectors are each designed for efficient uptake into specific target cells in diseased organs, including the following:

  • retina (intravitreal delivery)
  • heart (IV delivery)
  • skeletal muscles (IV delivery)
  • synovial joints (IV delivery)
  • lung airway (aerosol delivery)
  • liver (IV delivery)
  • brain (intrathecal delivery)

Highly efficient gene delivery:
Our vectors are designed for delivery to organs in the body by optimal routes of administration that will be safer and more effective for patients.

Specificity for the target diseased cells:
Our vectors are designed to avoid normal, non-targeted cells, thus increasing efficiency and decreasing possible safety risks (eg inflammation).

Resistance to inhibitory antibodies in patients’ blood:
In contrast to 1st and 2nd generation vectors, our vectors can be designed to avoid inhibition (ie “neutralization”) by antibodies present in most patients.

Strong intellectual property position:
Because 4DMT vectors are newly invented, and are customized and optimized, they are highly proprietary.