Mending the Broken Brain:
Novel Ways to Repair Brain Damage Using Stem Cells and Genes

Jakob Reiser, Ph.D.

Currently, most treatments to relieve damage to the brain and spinal cord caused by disease or accidents aim to relieve symptoms and limit further damage. But recent research carried out in laboratory animals has raised possibilities for actually repairing nervous system damage and disease.

Diseases Affecting the Brain
There are a wide variety of diseases that alter the normal function of the brain. These include tumors, genetic defects which often lead to abnormal brain development and mental retardation, and several common brain disorders such as Alzheimer's disease and Parkinson's disease. Three percent of the human population is estimated to be affected by serious brain diseases. In about one third of these cases, the cause appears to be genetic.

Therapies to Treat Brain Disorders
Owing to the complexity of the brain, most brain disorders lack effective treatments and therefore require the development of novel therapeutic approaches. Such approaches may include grafting to the brain of specific cells (cell-based therapy) or of therapeutic genes (gene therapy). Ongoing studies in experimental animals (mice, rats, and monkeys) show that these treatments can relieve disease symptoms. However, the long-term effects of such interventions are presently unknown, and because of ethical reasons it will be a challenge to extend these procedures to humans.

Cell-Based Therapies
Cell-based therapeutic strategies were originally established in patients afflicted with Parkinson's disease. Researchers have developed a way to treat Parkinson's disease in adults by injecting into their brains fetal neural cells that make dopamine, a brain chemical lacking in Parkinson's. Although initially quite promising, this study was recently phased out because the usefulness of the treatment was dubious. Compared to patients not receiving any fetal tissue, patients who received the fetal tissue sample showed no significant benefit in quality of life and absence of disease.

Brain Stem Cells
Future cell-based procedures to repair brain disorders may involve the transplantation of stem cells. Stem cells have been harvested from the brain, bone marrow, and embryos. Brain stem cells are rare and difficult to harvest. Studies carried out in mice show that such cells have a high degree of flexibility in terms of becoming other cells, i.e. they may turn into different kinds of brain cells depending on the location in the brain at which the transplanted cells arrive. Brain stem cells have also been isolated from human cadavers, and their biological features are being investigated.

Adult Stem Cells
Bone marrow-derived stem cells are also referred to as adult stem cells. Adult stem cells, like all stem cells, share at least two characteristics. First, they can make identical copies of themselves for long periods of time. Second, they can give rise to other cell types that have characteristic shapes and special functions. Adult stem cells are easily obtained from the bone marrow of a subject, and they can be maintained outside of the normal environment of the bone marrow in laboratory flasks. Given the right nutrients and growth conditions, such cells are capable of multiplying under these conditions, leading to large numbers of cells.

Embryonic Stem Cells
Stem cells can also be obtained from embryos. These are called embryonic stem cells. The embryonic stem cell is derived from one of the earliest stages of the development of an embryo called the blastocyst. Specifically, embryonic stem cells are derived from the blastocyst at a stage before it would implant in the uterine wall. Embryonic stem cells can self-replicate and give rise to all cell types in the body. Embryonic stem cells are obtained from aborted human fetuses.

Rebuilding the Nervous System Using Embryonic Stem Cells
Future research may show that repairing the brain could be effective using neural stem cells grown from embryonic stem cells. Research has shown that these stem cells can be directed to transform into other types of cells.

Despite the positive outlook, a plan to give federal funding to embryonic stem cell research has been delayed on the President's orders. Some groups oppose the research, because obtaining embryonic stem cells requires the death of a human embryo. These groups believe that adult stem cells, which can be isolated without the death of an embryo, should be studied instead. Many researchers, however, believe that embryonic stem cells hold greater promise for treating disease. A decision on this ethically and politically sensitive issue is expected soon.

Correcting Brain Disroders Before Birth
Using a technique similar to one used for Parkinson's disease, researchers are now exploring ways to correct brain disorders before birth. However, the technique, years away from being ready for human clinical trials, holds promise for treating diseases of the brain that develop because of flawed brain cells. Such an example would be Tay-Sachs disease, an inherited enzyme deficiency disorder in which a child is born normally but develops brain failure as an infant. The disorder occurs in about one out of every 3,600 children born to European Jewish families and French-Canadian families. It leads to mental retardation, blindness, and death by the age of four. In theory, injections of healthy neural stem cells could supplant the cells whose flaws cause Tay-Sachs and give the brain sufficient enzymes to develop normally after birth.

Gene-Based Therapy
In an alternative approach, genes can be delivered directly to the brain or spinal cord by gene transfer. This procedure involves gene delivery vehicles, commonly referred to as vectors.

Vectors Derived from Viruses
Virus-based gene transfer vectors have become vehicles of choice for the delivery of genes to the brain. This approach takes advantage of the properties of viruses as gene transfer agents. Viruses are essentially parasites that require the functions of a host cell in order to survive. They employ either DNA or RNA as the genetic material to encode a limited set of virus-specific functions. Virus-based gene delivery is highly efficient. Major concerns with this strategy are related to safety aspects and stability of gene correction over time. Initial studies in laboratory animals have been promising. Virus-based strategies involving cancer-destroying genes have been applied in patients with brain tumors, but the outcome of these treatment strategies were disappointing. However, similar studies carried out in rats with brain tumors were very successful. More studies are required with virus-based gene delivery strategies in the human brain to make this approach clinically useful.

Alzheimer's disease: Progressive dementia in elderly people

Blastocyst: An embryo made up of 30-150 cells

Bone marrow: Tissue in bone cavities containing stem cells, from which red and white blood cells originate

Brain stem cells: Stem cells found in adult brain tissue that can become other cells in the brain

Cell therapy: Delivery of cells to a patient to overcome a genetic abnormality or to combat a disease (e.g. cancer)

Gene therapy: Delivery of a functioning gene into the cells of a patient to correct a genetic abnormality or to provide a new function in a cell (e.g. cancer destroying gene)

Parkinson's disease: Progressive movement disorder

Stem cells: Cells that have the ability to divide indefinitely throughout the life of an organism and to give rise to many of the specialized cells that make up the organism

Tay-Sachs disease: Enzyme deficiency leading to brain failure

Vector: A disabled virus used as a vehicle to transfer genes into cells

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