8-4.2.4. Disrupting important genes in target cells

A gene that is introduced into any group of cells ideally needs to remain intact and continue to function inside the cell. For this the freshly introduced gene must integrate into the cells existing nuclear DNA which is a random process i.e. not site-specific that may lead to integration of foreign gene within the existing nuclear genes causing disruption of those genes in the cells.

Let us see the case of gene therapy:

Gene therapy is used to treat a number of children with X-linked Severe Combined Immune Deficiency (SCID). SCID patients, practically have no immune protection against microorganisms like bacteria and viruses. To escape infections and illnesses, they must live in a completely germ-free environment that is often impractical. A clinical trial for a gene therapy to restore the much needed function of a crucial gene, γ- c, to cells of the immune system was introduced. γ- c gene encodes for a subunit of cytokine receptors ( interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 ). Defect in this gene leads to with X-linked Severe Combined Immune Deficiency (SCID) due to blockage of T cell differentiation. This treatment appeared to be quite successful in restoring immune function in the recipient children with SCID.

But later, two of these children developed leukemia/blood cancer. It was found that the leukemia occurred because the newly transferred γ-c gene had incorporated into the wrong location, interrupting the function of another important gene that normally helps regulate the rate of cell division. As a result, the cells started dividing in an uncontrolled manner, causing the leukemia. Although doctors could treat the children successfully with chemotherapy, the development of leukemia attributable to gene therapy raised safety-related issues. The pioneering clinical trials for SCID-X1 gene therapy provided convincing proof of efficacy of gene therapy. However gene therapy suffers from the risk of insertional mutagenesis.

8-4.3 Future of Gene therapy

Gene therapy has not yet been realized to its full potential in clinical applications. The technology is still in developmental stage and yet to be developed. Between 1990 to 2000, several thousand patients were treated by gene therapy, mostly without long-term success.

The future successes of gene therapy also depend on the advancements in other relevant fields, such as medical devices, cell therapies, protein therapies and nanotechnology.

8-4.3.1. Medical devices

Medical advancements through innovative Medical Devices combined with biological proteins or drugs have become an exciting new area in treating patients with chronic diseases.

Advances:

• Stents containing proteins or drugs have been in use to treat cardiovascular diseases;
  
  
• Growth factors containing Collagen scaffold have been used to stimulate bone growth;
  
  
• Sustained release of   Nerve Growth Factor  attached to biodegradable polymer   microspheres for central nervous system cell stimulation and growth
  
  
• Bone and cartilage cells have been stimulated to grow with growth factors in representative matrix samples.
  
  
• Development of gene releasing scaffolds is also being attempted

In future, advances in these fields are likely to facilitate gene therapy. On the other hand, advances in the field of gene therapy will improve the treatment outcome in patients and may have stimulatory effects on growth of medical devices.

8-4.3.2. Protein therapies:

Protein therapies for diseases have been evolving due to better understanding of the molecular basis of many diseases. Insulin for diabetes & human   erythropoietin  for treating anaemias produced in cell culture using recombinant DNA technology (commercially available as Epogen) and various cytokines available for stimulating stem cells are few of the notable examples. The manufacture of such therapeutic proteins has been the rate-limiting step in these new classes of therapies into the clinic.

In future, better understanding of the molecular basis of human diseases will give additional therapeutic proteinaceous   products for ready to use clinical applications.