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 actuallyaddressing the condition.
To overcome the lack of truly curative and targeted treatments, a multidisciplinary Wyss team has developed a comprehensive gene therapy platform that combines a new computational target discovery platform with improved skin cell-specific adenovirus-associated (AAV) gene delivery vehicles, and a novel biomaterials-mediated local delivery of the genetic payloads to affected areas of the skin.
Leveraging a shared pathology
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. To identify specific molecular dysfunctions shared by monogenic diseases and aging skin, the platform applies a powerful new analytic technique – based on empirical modeling of dynamic systems – that is able to pinpoint mechanistic “drivers” of aging in a sea of multi-omics data obtained from high-throughput analyses of human skin transcripts, cellular morphology, and genome-wide association studies (GWAS).
Fortuitously, the Wyss team 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.
“Our novel dynamics framework dials in on the most promising single- and multi-gene candidates by skipping common statistical and machine learning techniques to instead focus on the core mechanisms of aging – how biological interactions change under the flow of time. We extract time-resolved interactions that evolve over the whole human lifespan,” said team member Ski Krieger, Ph.D. Combined with a powerful delivery technology, this gene therapy platform can approach unaddressed genetic disease indications in the skin and extend those same proven targets to common skin aging conditions affecting larger populations. In this way, the team’s approach departs from conventional concepts of gene therapy indications and stands to break into large markets not traditionally approachable by gene therapy.
Our computational approach revolutionizes the way we pursue aging target screens. We have a huge head start at the bench because our dynamic model pinpoints the subset of factors actually driving aging. We can prioritize and dig deep on this smaller set of drivers to build up an age-relevant fingerprint across multiple assays rather than being limited to higher throughput but lower-depth experiments.
DAVID THOMPSON, PH.D.
Going skin-deep with unprecedented targeting accuracy
The technology platform aims to solve transdermal delivery through formulation of skin cell-infecting AAV vectors into polymer devices. Gene therapy agents and pharmacological molecules are delivered directly into skin tissues via transient tissue microchannels, enabling rapid micro-scale mass transport that results in high local therapeutic concentrations. Unlike conventional injections, this polymeric delivery system is minimally invasive due to the superficial administration, which reduces pain and host immune response, a critical advantage if re-dosing of the therapy is required to improve its effects.
In contrast to the systemic delivery of gene therapies, our approach could have a highly favorable safety and efficacy profile. It requires much lower doses of the delivered gene therapeutic, avoids common problems of systemic therapies with liver and other toxicities, can be further combined with topical immune suppression to reach its full effect, and its success can be easily measured with regards to visible clinical endpoints.
DENITSA MILANOVA, PH.D.
Together, the safety and efficacy of the platform further enable development of age-related aesthetic and quality-of-life treatments, targeting novel skin aging genes identified through a uniquely powerful data analytics approach.
https://wyss.harvard.edu/technology/mrbl-next-generation-gene-therapy-for-molecular-skin-rejuvenation/
ارسال به دوستان