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Therapeutic Vector Evolution

What can 4D customized vectors do that first-generation vectors can’t do?

4D can select customized vectors from our library (pool) of 100 million novel vectors. But how are they customized? What can they do that first-generation vectors, found in nature, can’t do. Here is a partial list of what has been achieved with 4D selection technology, Therapeutic Vector Evolution, in the lab.

  1. Highly efficient gene uptake:
    Our vectors enable efficient uptake into target cells in a variety of organs, including:
    • lung (aerosol delivery)
    • retina (intravitreal delivery)
    • skeletal muscles (IV delivery)
    • synovial joints (IV delivery)
    • liver (IV delivery)
    • brain (intrathecal delivery)
    • heart (IV delivery)
  2. Highly efficient gene delivery:
    Our vectors enable delivery to organs in the body by administration methods that will be safer & more effective in the clinic for patients.
  3. Specificity for the target diseased cells:
    Our vectors avoid normal, non-diseased cells, thus increasing efficiency and decreasing any possible safety risks.
  4. Resistance to inhibitory antibodies in patients’ blood:
    In contrast to first-generation vectors, our vectors can be selected to avoid inhibition, or neutralization, by antibodies present in most patients.
  5. Strong intellectual property position:
    Because 4D vectors are newly created, and are customized and optimized, they will be highly proprietary.

How does 4D create and then select (identify) highly customized vectors through 4D Therapeutic Vector Evolution?

  1. We create a new library of about 100 million new vectors:
    The first step in our vector discovery platform technology is to create new vectors, and to create around 100 million of them. We create this massive and diverse vector pool through powerful diversity-generating methods created by many labs over the last decade. Current gene therapy products are built from about 10 different first-generation vectors. At 4D in marked contrast, we select the optimal customized vector for any organ out of a pool of about 100 million novel 4D vectors (our 4D “library” of vectors). This means that our 4D selection process is around 10 million times more powerful than first-generation approaches.
  2. We then carry out a selection process to isolate and identify the handful of vectors that has our desired characteristics:
    Our co-Founder Dr. David Schaffer and his lab team have discovered and perfected this process over the last 15 years at UC Berkeley and now at 4D. We repeatedly pass the vector pool through selection “filters” or “funnels” to progressively decrease the selection pool from 100 million vectors at the start down to a handful of 10-20 at the end. This entire process takes roughly 6-12 months on average. This process if akin to finding a needle (the customized vector) in a haystack of new vectors (the 4D vector library of 100 million novel vectors), and Dr. Schaffer and his team have become very good at this. In fact, to date they’ve been able to do this every time that they’ve tried. We have over 10 different selection processes underway to discover customized 4D vectors.
    4D Directed Evolution AAV Vectors Discovery Process
  3. Construction of the final therapeutic product:
    We then insert into the vector a gene “payload” (a DNA package to deliver) to replace the function of the defective gene in a specific disease; we insert the normal version of the defective gene. This last step in creation of a new 4D product is based on common lab techniques that were developed by the field over the last several decades. This is fast, straightforward and inexpensive.
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