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In Search of a Cure for CAH:  

Cell-Based Therapy and the Role of Stem Cells

by David T. Breault, M.D., Ph.D.

Stem cells are unique given their capacity (1) to give rise to other cells in the body and also (2) to replicate (self-renew) themselves, which provides for a continuous supply of new cells over time. Stem cells play important roles in the normal development of an individual and help maintain the essential functions of tissues and organs throughout one’s life.

Two major types of stem cells exist: Adult Stem Cells and Embryonic Stem Cells.

Adult Stem Cells are likely located within many tissues of the body serving as self-renewing cells over time. These cells have been definitely found in bone marrow and skin, although many more tissues are expected to contain adult stem cells. The clinical use of adult stem cells from bone marrow is well established to treat a variety of diseases.

Embryonic Stem (ES) Cells are derived from the early embryo, prior to the time of implantation into the uterus, and are able to become any cell within the body. Given this enormous potential, scientists hope to one day be able to coax ES cells to develop into a wide range of tissues, which will serve as the basis for treating many diseases.

Until recently, the generation of ES cells required the destruction of the early embryo, which raises significant ethical and moral issues for many individuals. Important advances have recently demonstrated that embryonic stem cells can be obtained from an 8 cell stage embryo without destroying it in the process.

The procedure to generate ES cells without destroying the embryo uses well-established methods to isolate a single cell from the embryo Stem Cell Research before it is implanted into the uterus. This technique is already widely employed by doctors to identify genetic mutations in embryos without their destruction. In addition, other promising approaches, which are designed to avoid the use or destruction of embryos, are currently being developed.

Cell-Based Therapy for Congenital Adrenal Hyperplasia (CAH)

The potential role of stem cells in the treatment of a wide variety of diseases, such as diabetes and Parkinson’s disease, has recently gained considerable attention. Cell-based therapy involves the use of highly specialized cells to replace a tissue’s missing function, such as hormone replacement.

CAH is an ideal condition for cell-based therapy given (1) the need for precise hormonal replacement, (2) the need to increase steroid levels during times of stress and (3) the highly complex daily variation in normal cortisol production rates. Each of these functions could ideally be provided by cells, which are responsive to normal hormonal signals.

Because individuals with CAH may have the ability to regulate cortisol in a normal manner, it is hoped that replacement with either (1) adult stem cells from the adrenal gland or (2) ES cell-derived steroid producing cells might restore normal adrenal hormone production. Ideally, cell-based therapy would also result in partial-to-complete adrenal androgen suppression from the patient’s own adrenal glands, which may be possible if sufficient cortisol levels are produced by these cells, though this remains to be proven.

Adult Stem Cells from the Adrenal Gland

The adrenal gland has long been assumed by researchers to contain a population of adult stem cells, which are thought to maintain this essential tissue for the lifespan of the individual. Proof of their existence, however, has been lacking. Recent studies from our laboratory have confirmed the presence of adult stem cells in the adrenal glands of rodents, raising the possibility that they also exist in humans.

While there is little doubt the tools required to study adult stem cells will emerge during the next decade, it is quite clear the field of adult stem cell biology, for tissues other than the bone marrow, is still in its infancy. In the meantime, EScell based strategies may offer the best potential for cell-based therapy for individuals with CAH and other conditions.

ES Cell-derived Steroid Producing Cells

The ability to coax ES cells into becoming cortisol-producing cells would represent a major step towards cell-based therapy for individuals with CAH. The methods required to turn ES cells into mature cells of any particular tissue will ultimately require determining how a tissue normally develops. For most tissues, including the adrenal gland, these methods are currently being established.

In our laboratory, we have developed a highly specialized screening system to help identify the specific developmental steps (factors) required for adrenal development. After identifying these factors, we hope to establish the methods required to coax ES cells into cortisol-producing cells and ultimately test their ability to restore normal adrenal function in model systems of CAH.

Advantages of Cell-Based Therapy for CAH

Unlike current cell-based therapies (like bone marrow transplantation), which require individuals to share common immune markers to avoid rejection, cell-based therapies offer the theoretical advantage of being tailored to the individual, thus potentially avoiding immune rejection and the need for immune suppressing drugs. For example, someday it may be possible to correct the genetic mutations causing CAH in individuals by applying gene therapy to an individual’s own stem cells (adult stem cells or ES cells), and therefore fully cure CAH.

The therapeutic potential of ES cells, whose unique power to self-renew and to develop into any human tissue or organ, is expected to transform the way that we treat, prevent and cure disease. Instead of drugs, cell-based therapy hopes to provide the means of restoring normal function to tissues and organs – including the adrenal gland. To help ensure that patients with CAH are not denied the potential future option of ES-derived cell based therapy, we have initiated fundamental research in this emerging area.

Dr. Breault is an Assistant in Medicine in the Division of Endocrinology at Children’s Hospital of Boston and an Instructor in Pediatrics at Harvard Medical School. In addition, he is an Affiliate of the Children’s Hospital Boston Stem Cell Program, and a member of the Harvard Stem Cell Institute and the International Society for Stem Cell Research.

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