Our Technology

Pluripotent Stem Cells possess both telomerase-mediated replicative immortality and regenerative potential, and are capable of producing all human cell types

 

Pluripotent Stem Cells possess both telomerase-mediated replicative immortality and regenerative potential, and are capable of producing all human cell types

In the mid-1990s, AgeX’s CEO Dr. Michael West, organized a collaboration with Drs. James Thomson, John Gearhart and Roger Pedersen that led to the first isolation of Pluripotent Stem Cells (PSCs). In contrast to other types of cells, PSCs are unique by at least two important criteria. The first criterion relates to the ability of pluripotent cells to proliferate, or make more copies of themselves indefinitely, that is to say they are “immortal”. The second criterion relates to the ability of PSCs to differentiate into any of the hundreds of specialized cell types in the body. This replicative immortality of PSCs facilitates the industrial scale-up of product. We believe many of these cell types have potential for regenerating function in tissues damaged by degenerative diseases when transplanted into the body.

Unlike immortal PSCs, adult stem cells typically have severely reduced scale-up potential because they are mortal. In addition, adult stem cells have passed the Weismann Barrier and are hence limited in their ability to regenerate normal tissue when transplanted in vivo. Therefore, we believe that PSC-based cellular therapeutics have significant competitive advantages over cell-based therapeutics being developed by the many adult stem cell companies.

 

PureStem® Technology

Regulatory approval of cell and tissue-based products requires high standards of quality control. In the case of stem cell-derived products, there is a high standard for insuring the known identity, purity, and reproducibility of the cells to be administered. Pluripotent Stem Cells (PSCs) such as Embryonic Stem (ES) cells and induced Pluripotent Stem (iPS) cells provide certain advantages over adult-derived cells when used in the manufacture of cell-based therapeutics for the treatment of age-related disease. These advantages include:

  • The replicative immortality of PSCs which facilitates the indefinite scale-up of PSC master cell banks for the manufacture of uniform product, as well as an immortal substrate for targeted genetic modifications.
  • Since most PSCs maintain long and stable telomere lengths, the replicative capacity of derived differentiated cell types is typically longer (and younger) than adult or even fetal-derived cells.
  • Using PureStem® technology, it is possible to clonally expand hundreds of purified, identified, and reproducibly scalable cell types that retain regenerative potential (i.e. they have not passed the regeneration limit).

PureStem® technology is based on the observation that early in our development, tissues in the human body are naturally comprised of highly proliferative cells with relatively long cell lifespans. Therefore, it is possible to generate single cell-derived (clonal) lineages of these cells in the laboratory, a process not easily achievable with cells derived from adult tissues which commonly senesce during clonal expansion.

In addition, adult tissues largely contain differentiated cells often with limited or no capacity of replication in vitro. As a result, the clonal expansion of our proprietary PureStem® lines allows not only a novel and more facile point of scalability, but also generates populations of cells that are multipotent instead of pluripotent, and hence markedly easier to define identity, purity, and potency.

We have studied the fate of over 200 diverse PureStem® cell lines in thousands of differentiation conditions. This was accomplished by thawing individual cryopreserved PureStem® cell lines, culturing them in the laboratory, and then exposing the cells to factors that differentiate cells such as protein, growth and differentiation factors, hormones, and/or small molecules implicated in causing cells to change from one type of cell into another (differentiation). Using individual cells from over 200 diverse PureStem® cell lines previously isolated and cryopreserved, we treated the diverse cells with thousands of differentiation conditions, prepared RNA, and determined the gene expression pattern of the cells using gene expression microarrays. These experiments have shown that the PureStem® cell lines display site-specific markers that identify not only the type of cells, but also where in the body the cells would normally reside. Therefore, in the example of cartilage cells, it was possible to produce diverse types of cartilage in this manner.

Applications outside of orthopedics, medical aesthetics, and certain ophthalmological applications are licensed from BioTime to AgeX. AgeX has chosen two applications for its initial product development based on unmet medical need along with other factors: First, Brown Adipose Tissue (BAT) cells for the treatment of Type II diabetes and second, vascular endothelial progenitors for the treatment of age-related ischemic disease such as that leading to myocardial ischemia and infarction. These cells will be formulated in a delivery matrix designated HyStem® to promote viability of the graft as well as to localize the cells to the intended site in the body.

 

induced Tissue Regeneration (iTR™)

The premise behind iTR™ is that aging, and in turn diseases of old age, are due to two characteristics that are present in the cells in our body when it is first forming but that are lost with time. These two characteristics are:

  • Replicative immortality of cells
  • Regenerative capacity of cells

Leveraging our assets in pluripotency and bioinformatics, we have performed research in cellular immortality and regenerative biology comparing cells in the first stages of life with those in old age. In 2010, while at BioTime, our scientists demonstrated the reversal of the developmental aging of human cells using transcriptional reprogramming technology. In 2017, we published certain genes that were turned off or turned on at the same time regenerative potential was lost.

We subsequently extended this research to determine whether reprogramming can be modified to only reverse the aging of cells back to a regenerative state, not back to pluripotency. We have utilized for example the gene COX7A1 as a marker of cells that have lost regenerative potential. Our proprietary formulation AGEX-iTR1547 has demonstrated initial capability of reducing the expression of the marker gene COX7A1 and we are currently performing research to optimize a potential pharmaceutical preparation to reverse the aging of human tissues and thereby restore regenerative potential.

When implemented in vivo, this partial reprogramming, or iTR, would be expected to induce tissue regeneration, and when combined with telomerase, could modulate both cellular immortality and regenerative biology for therapeutic effect.

In addition, Renelon™, a first generation product candidate, utilizes a repurposed drug formatted in HyStem® and is planned for initial development as a device for topical application. While not capable of fully transporting cells back to a regenerative state, the anticipated ability of Renelon™ to impart scarless repair could provide significant benefits to patients.

 

UniverCyte™

UniverCyte™ is a proprietary technology to modify cells such that they can potentially be transplanted into all patients “off-the-shelf”, that is, without the normal need to match cells to the patient. The process uses a molecule called HLA-G. In nature, HLA-G’s primary function is to prevent immune rejection of a baby by the mother. Therefore, we believe our HLA-G modified PureStem® cell therapies will utilize a natural pathway of preventing transplant rejection and hence may have certain benefits over current immunosuppressive strategies.

 

HyStem® Delivery Technology

HyStem® is a patented biomaterial that mimics the extracellular matrix, the structural network of macromolecules surrounding cells in the body. The extracellular matrix is essential for normal cellular function and survival of transplanted cells. Many tissue engineering and regenerative cell-based therapies are expected to benefit from the delivery of therapeutic cells in a matrix for precise localized delivery and survival. HyStem® is a unique hydrogel that has been shown to support cellular attachment in the body. Current research at leading medical institutions has shown that HyStem® is compatible with a wide variety of cells and tissue types including those of the brain, bone, skin, cartilage, vascular system, and heart.

The technology underlying AgeX’s HyStem® hydrogels was developed at the University of Utah and has been exclusively licensed to BioTime for human therapeutic applications and sublicensed to AgeX for certain fields. The HyStem® technology is based on unique thiol cross-linking chemistry to prepare hyaluronan-based matrices/hydrogels. Since the first published report in 2002, there have been numerous academic scientific publications supporting the biocompatibility of thiol cross-linked hyaluronan-based matrices and their applications as medical devices and in cell culture, tissue engineering, and animal models of cell-based therapies.

Due to the unique cross-linking chemistry, HyStem® matrices have the ability to be safely combined with living cells and subsequently injected or applied locally as a hydrogel which allows the gel to conform to the three-dimensional contour of a tissue. This property of HyStem® offers several distinct advantages over other matrices. For example, in addition to the potential to embed living cells in a cross-linked matrix, HyStem® can provide a slow-release matrix for the delivery of bioactive molecules. Building upon this platform, we plan to use HyStem® for both cell-based therapy as well as for the delivery of iTR™ factors.

The building blocks for HyStem® hydrogels may vary with the application but typically include some combination of hyaluronan, gelatin and heparin, each of which has been thiol-modified. Hydrogels are formed by cross-linking mixtures of these thiolated macromolecules with polyethylene glycol diacrylate (PEGDA). The rate of gelation and hydrogel stiffness can be controlled by varying the amount of cross-linker. An important attribute of HyStem® hydrogels is their large water content, over 98%. As a result, these hydrogels have a high permeability for oxygen, nutrients, and other water-soluble metabolites.