Fight Aging!

MRBL is one of the many projects relevant to the treatment of aging that is in George Church's orbit. This is a collection of gene therapy technologies intended for delivery of vectors to areas of skin directly, coupled with analysis of age-related and disease-related gene expression changes in skin cell populations to provide targets. It is a viewed as a basis for approaches in cell reprogramming that could make aged skin cells behave in a more youthful fashion, overriding their response to the age-damaged local environment.

In terms of mechanisms known to be of interest in aging, upregulation of collagen production is an obvious goal, generally agreed upon to be beneficial if achieved. A more interesting but more challenging result to aim for would be the deposition of elastin in a structurally correct manner. Beyond these two, there are many other more subtle issues in cell misbehavior related to the aging of skin, from stem cell activity to coordination of wound healing in the dermis and epidermis.

That said, it isn't clear that forcing more a youthful behavior in cells via gene therapies is the best way forward in all matters relating to aging. It neglects root causes in favor of trying to override them selectively, allowing those root causes to continue to produce all of their other consequences. Chronic inflammation, for example, has a broadly negative impact on tissue function in skin, as is also the case in other organs. Clearing senescent cells, and removing other causes of systemic inflammation, are likely better approaches than trying to force cells to perform correctly, one gene at a time, in an inflamed environment.

MRBL: Next-Generation Gene Therapy for Molecular Skin Rejuvenation

The skin is the largest organ in the body, and carries out multiple vital functions, including protective barrier functions against the loss of moisture and mechanical, UV, and other injuries, immune defense functions, as well as sensory functions. For maintaining its integrity and multifaceted performances, skin relies on a range of different cell types that compose and support its layered organization, each expressing specific molecules that together facilitate physical cell interactions and communication between them, as well as specialized functions.

The gradual decline in the production of many of those molecules is associated with the natural aging process of skin. Separately, a plethora of skin diseases are driven by mutations in single genes that can strike much earlier in life. In both cases, targeted therapeutics that could slow skin aging and directly interfere with the disease pathology of monogenic skin diseases are not available. Commonly applied treatments are merely palliative, reducing the severity symptoms or simply masking the visible damage caused to the skin without actually addressing the condition.

To overcome the lack of truly curative and targeted treatments, a multidisciplinary team has developed a comprehensive gene therapy platform that combines a new computational target discovery platform with improved skin cell-specific adenovirus-associated virus (AAV) gene delivery vehicles, and a novel biomaterials-mediated local delivery of the genetic payloads to affected areas of the skin. Strategically targeting both disease (short-term) and aging (long-term), this next generation skin gene therapy platform builds on the insight that the pathology of genetic diseases often recapitulates specific age-related degenerations.

Fortuitously, researchers found that key targets in aging biology could be leveraged as therapeutics for monogenic diseases, as the genes affected in such diseases were also powerful determinants of the aging process. Using their new-found understanding of aging dynamics, the team has built a time-resolved genetic network of skin aging, and is currently validating novel age-driving genetic targets identified from the resulting map in cell and animal studies.

Denitsa Milanova on MRBL - Gene Therapy for Skin Rejuvenation

I'm working on an Institute Project called MRBL, which essentially enables in situ genetic engineering of the skin. It's a platform technology and has a variety of applications. We started the project looking at the hardest problem - how to solve skin aging at the molecular level. Our gene-potentiating technology could make skin cells go back to their younger state, causing a true rejuvenating effect, and we're trying to get there by modifying the levels of the right fingerprint of genes in the skin.

This technology can also be applied to monogenetic skin diseases, which are diseases that are controlled by the malfunction of a single gene. These conditions manifest in phenotypes like blistering skin and numerous open wounds. With MRBL we are creating novel therapeutics that can correct the levels of such dysfunctional genes or even permanently correct mutations causing injured skin using a skin cell-specific, minimally invasive, adenovirus-associated (AAV)-based gene delivery system.

Beyond that, we are using the same technology to try and leverage the skin as a bioreactor for the production of neutralizing antibodies directly in the body that could help fight HIV, COVID-19 or other infectious diseases. In these instances, the skin is not being treated because it is sick or aging, but instead used as a "factory" to produce therapeutic antibodies or even foreign proteins that stimulate the immune system in a protective way.