If a cell lacks an allele that encodes a functional product, an optimal treatment would be to provide a functional allele. The objective of gene therapy is to add a new gene that will be expressed in appropriate cells in a patient. What cells should be targeted? There are two approaches:

There are two approaches to somatic cell gene therapy:

Armed with knowledge of how genes are expressed (see Chapter 14) and regulated (see Chapter 16), physicians can design a therapeutic gene that contains not only a normal protein-coding sequence but also other sequences—such as an appropriate promoter—required for the gene’s expression in targeted cells.

A major challenge has been getting the therapeutic gene into cells. Uptake of DNA into eukaryotic cells is a rare event, and once the DNA is inside a cell, its entry into the nucleus and expression are rarer still. One solution to these problems is to insert the gene into a carrier virus (a viral vector) that can infect human cells but has been altered genetically to prevent viral replication. An example is the DNA virus called adeno-associated virus, which has been widely used in human gene therapy clinical trials. This virus has a small genome that can be spliced into a human gene; infects most human cells, including nondividing cells such as neurons; is harmless to humans; does not provoke rejection by the immune system; and enters the cell nucleus, where its DNA with the new gene can be expressed.

333

Adeno-associated virus has been used successfully in human gene therapy targeting Parkinson’s disease (Figure 15.18). Parkinson’s disease is a neurological condition that affects about 1 in 200 persons in their 60s, and 1 in 25 persons in their 80s. Its symptoms include muscle stiffness and shaking and—in about half of the patients—dementia. Patients with Parkinson’s disease produce inadequate amounts of the neurotransmitter γ-aminobutyric acid (GABA) in a particular part of the brain due to degeneration of the neurons that normally produce GABA. Low GABA levels result in poor coordination of movement. Raising GABA levels would thus be a reasonable approach to treatment. Recognizing that synthesis of GABA is catalyzed by the enzyme glutamate decarboxylase, a team led by Dr. Andrew Feigin at the Feinstein Institute in New York packaged a glutamate decarboxylase gene into adeno-associated virus that was then injected into the affected part of the brain. After six months, the patients who received the virus-encapsulated gene had increased levels of GABA and significant improvement in their disease symptoms. Other diseases being treated with gene therapy using this virus include cystic fibrosis, hemophilia, and muscular dystrophy. While this looks exciting on paper, bear in mind that this type of therapy is very rare, at the frontier of medicine. We aren’t close to the day when we can go see our local gene therapist for a cure.