Control of gene expression is fundamentally important in the development of both in vivo gene therapy and ex vivo gene modified cell therapy products. Synpromics' technology creates the unique opportunity for therapeutic developers to improve product function through targeted expression level, cell type(s) selectivity, and construct size optimization.
Challenges in Cell and Gene Therapy
There have traditionally been three major challenges in the development of cell and gene therapy: delivery, expression and immunity. Novel vector systems including vector types and regulatory elements are presently being widely developed to better deliver the gene of interest to the correct cell or tissue type, at the optimal expression level and for the appropriate duration to elicit a therapeutic effect. These new promoters are required to drive efficient, yet finely tuned, gene expression so that the therapeutic effect is directed and durable. Finally, given that the target gene is often delivered using immunogenic vectors (both viral and cellular) and that the therapeutic gene is often new to self, long-term immune responses to the therapeutic cassette need to be minimised.
Synpromics' Technology Improves Gene Therapies
The technology created at Synpromics enables the design of novel synthetic promoters:
- selective to tissue, single, dual or multiple cell types (e.g. liver, muscle, CNS, hepatocytes, motor neuron + muscle, etc), developmental stage (e.g., lineage specificity in stem cells, etc), cell state (e.g., pathogen-infected, diseased, etc)
- variable expression levels - strong, medium, low activity
- various tailored sizes (bp)
- designed to be regulatable, inducible, or have a safety switch feature
Synpromics have designed liver-specific synthetic promoters with a wide range of activities. Shown are the results from in-vitro luciferase assays for eleven different Synpromics promoters (blue bars) compared to CBA and a benchmark liver promoter, referred to as “Control” (orange bars). The size of the synthetic promoters ranges from 250 to 690bp.
Synpromics have designed muscle-specific synthetic promoters with a wide range of activities. Shown are the results from in-vitro luciferase assays for seven different Synpromics promoters (blue bars) compared to a benchmark muscle promoter, referred to as “Control” (orange bar). The size of the synthetic promoters ranges from 515 to 940bp.
Our synthetic promoters can be designed to optimize the level of expression through defined activity levels in one or more cell type, can be constitutive or inducible to improve therapeutic effect with durable expression and can be optimized for size. Finally, by enhancing the specific activity of the promoter it should be possible to reduce vector dose, thereby increasing the safety profile of the therapeutic, lowering immunogenicity and reducing off-target side effects.
A Promoter for Any Cell Type or Condition
Synpromics generates panels of tailored promoters, each with unique sequences and each driving expression to a defined level. Promoters can be designed to any length, which is important for vectors based on the adeno-associated virus, which has a very short genome and consequently reduced capacity for the therapeutic cassette. Smaller promoters mean that there is more space for the transgene and other important elements required for optimal control of its expression. Novel promoters also can increase stability of the therapeutic product, as multiple genes can be delivered by single vectors into a cell, thus preventing instability through recombination.
In addition, Synpromics creates synthetic promoters with novel sequences that do not exist in nature. This improves the patentability of any therapeutic construct comprising a Synpromics promoter, as the technology facilitates the discovery of promoters consisting of unique combinations of regulatory elements with the desired activity.
Synpromics' unique approach to synthetic promoter development means that it is now possible to develop new promoters to improve therapeutic cell and gene therapy products. We can either select and out-license candidates from existing promoter libraries or alternatively engage in a design and development program to deliver promoters with particular criteria that are unique to the specific application.