Future Therapies Using Implanted Engineered Cells as Protein Factories

Biotech developers have long hoped to build on the historical successes of protein therapeutics by addressing the limitations of drug delivery. These therapies are typically delivered by intermittent infusions or injections, resulting in wide peaks and troughs of protein levels in the body. The varying levels prevent these treatments from freeing patients from the symptoms of their disease. In addition, the process of administering therapies by infusions or injections, required as often as several times a week, is a significant disruption to the patient’s quality of life.

Gene therapies have promising potential as a method for generating proteins within the body. While there have been recent successes in a few therapeutic applications, broad use of gene therapy remains a major challenge. Another approach has been to implant allogeneic, or genetically dissimilar, cells engineered to act as “protein factories.” The problem, however, is that implanted allogeneic cells are rejected by the immune system. Even if the implanted cells are encapsulated within a device, a foreign body response from the immune system typically results in a fibrotic response that effectively kills the cells.

Following a focused, high-throughput search for biomaterials that can evade this fibrotic response, researchers at the Massachusetts Institute of Technology have discovered a new set of compounds that do not elicit a foreign body response when implanted. These biomaterials permit the development of a new category of treatment with the ability to deliver therapeutics either at a constant rate or under programmable conditions by using implantable cells as protein factories. Sigilon Therapeutics was founded to combine these new “Afibromer” biomaterials with the cell engineering required for successful clinical development of effective therapeutics.

Allogeneic cells programmed to express therapeutic protein can be loaded within a small spherical capsule made from the Afibromer biomaterials. These capsules can then be implanted into appropriate locations in the body. For some applications currently in development, the 1.5-millimeter diameter Afibromer beads could be implanted using a straightforward injection, or for specific locations, a minimally invasive laparoscopic surgical procedure. With the implants in place, proteins produced by cells within the beads would be secreted out of these engineered cells and enter circulation. The dose for each patient can be adjusted both by varying the number of cells loaded onto a bead and by varying the number of implanted beads. One of the limitations of gene therapies is that the dose cannot be tailored to individual patients. The ability to adjust the dose with Afibromer biomaterials is, therefore, an advantage-particularly for pediatric patients who may require dose adjustments as their body grows. Afibromer protein factories represent a flexible and programmable alternative to gene therapies, but they can also be used to “top up” gene therapy doses in the future and thus be a complementary approach.

Another issue is that gene therapies may require immunosuppressive therapy to prevent immune responses against gene therapy vectors, particularly in a re-dosing scenario. With Afibromer technology, immunosuppressive therapy is not required.

Extending beyond published data (1, 2) using animal models of diabetes, unpublished preclinical data demonstrate that these Afibromer protein factories can remain functional for at least a year, producing a variety of therapeutic proteins. This is a proof-of-concept minimum limit to the duration of the cell implant approach. The goal for this therapy would be to provide a stable level of therapeutic protein for multiple years. As with any new technology, finding the appropriate real-world application is key to maximizing clinical benefit and commercial success. Currently, the researchers are working to develop treatments for diseases with significant co-morbidities and patient burdens. The plan is to bring a lead product to the clinic in two to three years. Once the approach is validated in clinical studies, it is expected that this technology will have use in a wide variety of applications.

References

1. AJ Vegas et al., Nature Medicine 22, 306–311 (2016) doi:10.1038/nm.4030.
2. AJ Vegas et al., Nature Biotechnology 34, 345–352 (2016) doi:10.1038/nbt.3462.

About the Author 

Devyn Smith, PhD, is chief operations officer and head of strategy of Sigilon Therapeutics.

Article Details

Pharmaceutical Technology
Vol. 42, No. 4
April 2018
Pages: 32–33

Citation
When referring to this article, please cite it as D. Smith “Future Therapies Using Implanted Engineered Cells as Protein Factories,” Pharmaceutical Technology 42 (4) 2018.