Genetic Disorders & Gene Therapy

What is gene therapy?

Where does gene therapy connect to genetics, and how?

Why utilize gene therapy at all and not traditional methods, such as drugs and medications?

How does gene therapy work?

 Genes are found in chromosomes, and are basic physical and functional units of heredity. They’re specific sequences of bases which code to make proteins. Genes are given importance because of proteins; it’s proteins that perform most of the functions of life. Proteins also work to build our numerous cellular structures.(Citation 4)

When genes are altered so that encoded proteins are unable to carry out their normal functions, genetic disorders can result. These alterations can form on several different levels or scales. A point mutation in a gene (i.e. when a single nucleotide is mistakenly altered during synthesis) is not usually serious.  For example, Sickle-cell disease, which is an exception because it is in fact a serious disease, is caused by a point mutation on β-globin chain of hemoglobin. Hydrophilic amino acid glutamine acid is replaced with hydrophobic amino acid valine in the sixth position. Mutation occurs on Chromosome 11. In Sickle-cell anemia, the red blood cells turn sickle-shaped, thereby causing problems in blood flow and oxygen-carrying capacity. People who inherit a sickle hemoglobin gene from one parent and a normal gene from the other parent have a condition called sickle cell trait

 Other mutations can occur on a larger basis, sometimes, for example, due to the addition of an extra nucleotide in a gene or the removal of the nucleotide. Both of these can shift the entire synthesis reading frame from the point they are removed or added.

Genetic disorders can be classified on basis of :

Level 1: Single Gene Disorders

Disorders which result when a mutation causes the protein product of a single gene to be altered, differentiated, or missing.

Level 2: Chromosome Abnormalities

In the Level 2 disorders, entire or whole chromosomes, or large segments of the chromosomes, are missing, duplicated, or altered.

Level 3: Multifactorial Disorders

Multifactorial disorders are those which result from mutations in multiple genes. They’re complex, often coupled with environmental causes.(Citation 5)

Genetic disorders are often life-crippling. Most of them are present at birth or sometime early in life. Many of them result in life-threatening situations, mental, physical, or sexual disability, or even eventually fatal turns.

What makes genetic disorders even worse is that some of them can be inherited; this means that certain members of the populations can be only carriers for a genetic disease, thus holding the genetic disease without actually experiencing it. Thus, a disease can unknowingly pass on until it affects a generation.

So, the key question is: what can be done about genetic disorders?

 Gene therapy is defined as a “technique for correcting defective genes responsible for disease development”.(Citation 6)

Gene therapy involves, in its most basic sense, the application of treatment on a genetic level in order to provide therapy or cure for genetic diseases.

There are several different types of approaches to gene therapy. One common approach involves simply replacing a faulty gene with a good gene with the use of manipulated vectors, such as viruses, or even microsurgery, using nanotechnology. Another method involves editing the chromosome itself in order to remove any defective genes. Genes causing a disease can be “switched” on or off. Genes could also be reverse-mutated back into normal genes.

What differentiates gene therapy from other types of therapies? Firstly, gene therapy is a rather more permanent solution. Turning off the gene causing a disease, such as cancer, for example, would be more effective than providing constant non-genetic therapeutics for the cancer. As the creators of the University of Utah’s “Learning Genetics” website write, gene therapy is akin to fixing a broken window: one has the option of either repairing the cracked window with tape, or putting in an entirely new window. In a similar way, gene therapies can involve replacing the faulty gene entirely, thus preventing future occurrences or remissions of the disease. Whereas most drug-based approaches only serve to cure symptoms, gene therapy provides a way to fix a problem at its source.(Citation 7)

  A visualization of germ line gene therapy. In germ line gene therapy, note that the healthy child will also pass on the corrective genes to his or her children. At the same time of added benefit, germ line gene therapy is also highly controversial and therefore not as rigorously

 Ex-vivo somatic gene therapy. Somatic gene therapy is mostly performed in developed humans and provides the healthy gene for only the patient. His offspring will not carry the corrective gene.

  A model of ex-vivo gene therapy. Ex-vivo gene therapy is more commonly used.

Shown on the left side is an in-vivo approach to gene therapy. Here, the therapeutic nucleic acid is inserted directly into the patient. The gene is packaged into one of several types of vectors and delivered with a device to a target organ. In the visual shown, the gene is incorporated into a plasmid and delivered to liver via a catheter in portal vein.

 A globular conformation consisting of a 500-kilobase gene-rich domain. It's located on human chromosome number 16. Proteins are vital to functioning; proteins are made when genes are synthesized.

 Several types of mutations can lead to problems in a gene. Notice how some mutations change the amino acid composition of the synthesized protein.

 Neurological diseases caused by triplet repeat amplifications in chromosome locus areas.

 A cause of genetic disease: non-disjunction in chromosomes. Normal meiosis is shown in A). B) shows non-disjunction in meiosis I, cellular division process, and (C) shows non-disjunction in meiosis II, the second phase of meiosis.

  A potential gene therapy designed and developed by ArmaGen to cross the blood-brain barrier in order to rescue dying nerves.

• Ex-vivo Gene Therapy - In ex-vivo gene therapy, cells are first cultured or synthesized outside of an organism (for gene therapy), and then inserted into the organism to provide the treatment. Ex-vivo gene therapy is more common than in-vivo therapy (explained below). Ex-vivo therapy significantly reduces many risks involved with gene therapy. At the same time, however, ex-vivo gene therapy holds some limitations - indirectly introducing the desired-containing cells into an organism may trigger immune responses. The cells also may not function as desired, malfunction, or not entirely work at all.
• In-vivo Gene Therapy - In in-vivo gene therapy, the gene is directly delivered to the organism, such as through a vector or other means. In-vivo gene therapy is less commonly used than ex-vivo gene therapy. In-vivo gene therapy holds more risks than its ex-vivo counterpart, such as a possible immune reaction from the organism. Vectors used in in-vivo gene therapy include viruses, bacterial plasmids, nanoparticles, and more.(Citation 8)
  

 Video Citation 1