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Gene Therapy


The goal of gene therapy is to insert a healthy copy of a gene into a cell that has a faulty gene. If the gene doesn’t integrate properly, it produces its protein for only a short time before being turned off or broken down within the cell. To ensure a long-term cure, the gene must position itself into a chromosome, where it remains permanently integrated. It will be passed on when the cell divides.[1]

In general, the basic steps of gene therapy are:[2]

  1. Identifying the faulty gene that causes a specific disease.

  2. Pinpointing the location of the affected cells.

  3. Having a healthy version of the gene available.

  4. Delivering the healthy gene to the cell.

Basic methods:

Gene therapy uses vectors to spread missing genes to individuals. A vector is an altered organism that carries the gene into the cell, while not causing the disease itself. Certain viruses act as vectors in gene therapy, attacking their hosts to insert their genetic material into the genetic material of the host.[3]

To insert a new gene into a cell, a "carrier," called a vector, is needed to deliver the DNA. The vector is genetically engineered to contain the new gene. Certain viruses are often used as vectors because they can infect a cell and integrate their DNA into the cell's genetic material. The viruses are modified so they can't cause disease when used in people. If the treatment is successful, the new gene delivered by the vector will become part of the cells' DNA and make a functioning protein. Three types of viruses are used in gene therapy:

  • Retroviruses, which integrate the genetic material, including the new gene, into the chromosome.[4] With the retrovirus vector, the missing gene is replicated within the cell when the cell divides.
  • Adenoviruses, which introduce their DNA molecule into the host, but the genetic material is not integrated into the host cells’ genetic material. So when the cell is about to divide, the extra genes are not replicated. Because of this, the adenovirus will require regular doses to add the missing gene.[5]
  • Adeno-associated viruses (AAV) do not cause immune responses from the cells that have been altered. The main disadvantages of using AAV are the difficulty in producing it and the small amount of DNA it can carry. Most people treated with AAV do not have an immune response to it.

The two basic methods of inserting altered genes are:

  • n vivo, which inserts genetically altered genes directly into the patient. The vector carriers have a difficult task to complete: they must deliver the genes to enough cells for results to be achieved, and they have to remain undetected by the body's immune system.
  • Ex vivo, which removes tissue from the patient, extracts the cells in question, and genetically alters them before returning them to the patient. This technique is best used for diseases (e.g. blood) where the desired cells can be extracted easily.[6]

Alpha-synuclein inhibitors:

The presence of intracellular inclusions and Lewy bodies in the dopaminergic neurons of the brain’s substantia nigra is characteristic of Parkinson’s disease. These deposits are primarily composed of clumps of alpha-synuclein and their presence is believed to play an important role in Parkinson's. Beta- and gamma-synucleins inhibit alpha-synuclein fibril formation.[7]  Identifying inhibitors of alpha-synuclein could lead to new treatments for Parkinson’s.

Additionally, defective genes that regulate the molecules of alpha synuclein and parkin may be responsible for a number of early-onset Parkinson’s cases. Genetic abnormalities of the alpha synuclein protein have been detected in some early-onset Parkinson's patients of European descent.[8]

GAD gene therapy:

Following successful animal tests on rats and monkeys, doctors performed the first-ever human trial of gene therapy for Parkinson’s disease. The technique used the GAD gene delivered by a modified virus and functioned effectively on rats. The treated rats did not continue deteriorating, unlike the untreated control rats. Tests on monkeys showed the therapy to be safe. In September 2004 the first patient, Nathan Klein, had passed one year without a hitch. He claimed to have experienced an improvement of 40–60% in overall symptoms when he is on his medication, and 10–20% when he is not.[9]

The minutes of the Recombinant DNA Advisory Committee’s meeting, March 9-11, 2004, state: “Analysis of results to date show no surgical complications, no local inflammation, no fevers or change in laboratory values, no radiographic evidence of toxicity, no study-related AEs, and one serious adverse event (SAE) unrelated to the intervention, which was a result of hospitalization.”[10]

Rnai (RNA interference) technology:

RNA interference (RNAi) is a mechanism in which the presence of small fragments of double-stranded RNA (dsRNA) whose sequence matches a given gene interferes with the expression of that gene. Gene expression is the process by which a gene's information is converted into the structures and functions of a cell.[11]

Potential benefits:

  • Repairs faulty genes

  • Regenerates repaired cells

  • Provides a cure


  • “The immune system may respond to the healthy gene copy that has been inserted and cause inflammation.”

  • “The healthy gene might be slotted into the wrong spot.”

  • “The healthy gene might produce too much missing enzyme or protein, causing other health problems. “

  • “Other genes may be accidentally delivered to the cell.”

  • “The deactivated virus might target other cells as well as the intended cells.”

  • “The deactivated virus may be contagious”


  • Finding a vector that can be turned off if necessary

  • Doing safety and toxicity studies of vectors

  • Discovering a method that will safely deliver and regulate the genes introduced into the central nervous system

Current research involving human beings:


Avigen’s AV201 is designed to restore the effectiveness of levodopa by putting the gene for AADC into the striatum of the brain of trial participants who have advanced Parkinson’s disease. The goal is for the trial participants to respond to a lower dose of levodopa and not experience dyskinesia.[13]

  • Neurologix

Neurologix had a 12-patient, dose-escalating Phase I trial using a viral vector (the non-pathogenic adeno-associated virus, or AAV) for the treatment of Parkinson's disease. In the trial, the vector was injected into a specific target site in the brain in order to transfer a gene to treat PD.

This treatment appears to be safe and well-tolerated by the 12 participants, who have advanced PD. Additionally the participants had better motor function on the side of body which correlated to the treated part of the brain."[14]

  • Ceregene

In September 2005, Ceregene announced a Phase I study of CERE-120 to treat Parkinson's disease.  CERE-120 uses an  adeno-associated virus (AAV) type2 vector delivery system to deliver the neurturin (NTN) gene. NTN is a naturally occurring gene that encodes the NTN protein that maintains survival of dopamine-producing nerve cells that are required for normal bodily movement and are the nerves that degenerate in Parkinson's disease patients. Neurturin and GDNF are members of the same protein family and have similar pharmacological properties.[16]

Research on animals:

  • In two separate studies, scientists have used gene therapy to renew brain cells and restore normal movements in monkeys and rats with a drug-induced form of Parkinson's disease.

Scientists believe the protein, glial cell line-derived neurotrophic factor (GDNF), preserves brain cells and might provide protection against Parkinson's disease. The gene therapy used in monkeys represents a different way to deliver the GDNF than were used in the Amgen GDNF clinical trials. This new method causes the body to produce GDNF naturally. This method of delivering GDNF to the brain also produces more manageable levels of the protein in the brain.

In separate experiments with rats, researchers used gene therapy to completely reverse dyskinesias in some of the animals. Before receiving the treatment, all rats had limited use in their left paws. After the treatment, the animals showed complete recovery in their paws.[17]

  • Scientists at the École Polytechnique Federale de Lausanne (ÉPFL) in Lausanne, Switzerland, have conducted novel experiments that might one day lead to gene therapy treatment options for patients with Parkinson’s disease. They found that viral delivery of a gene associated with Parkinson’s disease protected neurons from degeneration.[18]

Promising research

  • Northwestern University neuroscientists have originated a method that will safely deliver and regulate genes that have been introduced into the central nervous system to treat Parkinson's disease and other neurodegenerative diseases. This overcomes a major obstacle in gene therapy–that of being able to turn off the vector in the gene.

Martha C. Bohn and her colleagues at Northwestern University have been working to develop viral vectors that are a safe way to deliver GDNF, as well as other therapeutic genes. The researchers used the AAV vector in these experiments. The AAV vector is safe and already approved for use in several clinical trials in the brain of humans. However at this time there is no vector approved for use in clinical trials in which the gene can be turned off.

In their experiments on rats, Bohn and co-researchers were able to turn off up to 99 percent of the vector-introduced gene with small doses of doxycycline. Doxycycline is a drug already approved by the Food and Drug Administration. It has no side effects.

Thorough safety and toxicity studies of the new vector will still need to take place. This treatment is not ready to be tested on humans yet.[19]

  • Alnylam Pharmaceuticals, Inc and RNAi technology: Alnylam Pharmaceuticals, Inc. and the Mayo Clinic are collaborating in a research effort using RNAi technology. As part of their collaboration, Alnylam will provide RNAi technology and fund research at Mayo Clinic to develop a drug that suppresses the expression alpha-synuclein, found to be over-expressed in Parkinson's patients.

Under the terms of the research collaboration, Alnylam will identify, synthesize and provide RNAi-based drug compounds targeted to alpha-synuclein. In a series of in vitro and in vivo studies, the Mayo Clinic will test and select the RNAi compounds for efficacy. It is anticipated that “therapy to reduce alpha-synuclein gene expression will benefit not only Parkinson's disease patients who carry the rare gene mutation, but also persons who carry common susceptibility variants of the gene, or persons who aggregate the alpha-synuclein protein via other genetic and non-genetic mechanisms."[20]



[1] Stanford researchers develop gene therapy technique that sharply cuts risks 10-14-02; Stanford U medical center

[2] Gene therapy; Center for Genetics Education; retrieved date: March 10, 2005

[3] Gene Therapy; retrieved date: March 10, 2005

[4] My DNA.com: Genetics 101: Gene Therapy; retrieved date: March 10, 2005

[5] Wikipedia: gene therapy; retrieved date: March 10, 2005

[6] The Columbia Electronic Encyclopedia, Sixth Edition Copyright © 2003, Columbia University Press. Licensed from Columbia University Press. All rights reserved.

[7] Uversky, V. N., J. Li, et al. (2002). "Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins." J Biol Chem 277(14): 11970-8.

[8] Parkinson's Disease; March 2002; WHAT IS PARKINSON'S DISEASE AND WHAT CAUSES IT?

[9] http://www.rds-online.org.uk/pages/headline_detail.asp?i_PageID=144&i_ToolbarID=6 RDS: Parkinson’s disease; retrieved dated: March 15, 2005

[10] RECOMBINANT DNA ADVISORY COMMITTEE; NIH Minutes of Meeting: March 9-11, 2004

[11] Wikipedia: RNAI

[12] Gene therapy; Center for Genetics Education ; retrieved date: March 10, 2005

[13] Avigan, Ongoing Clinical Trials : Parkinson’s Diease; retrieved date: March 10, 2005

[14] Neurologix announces positive results of gene therapy clinical trial in Parkinson's disease;  September 21, 2005

[15] Neurologix announces positive results of gene therapy clinical trial in Parkinson's disease;  September 21, 2005

[16] Ceregene Reports Initiation of Phase 1 Clinical Trial of Novel Gene Therapy for Patients With Parkinson's Disease; September 21, 2005

[17] University of Florida Health Center; Gene therapy for Parkinson's disease moves forward in animals John Pastor, jpastor@vpha.health.ufl.edu; Feb. 8, 2005

[18] Gene Therapy Shows Promise in Model of Parkinson’s Disease; November 29, 2004

[19] Regulatable gene therapy may advance treatment of Parkinson's disease; 05 Jun 2004

[20] Mayo Clinic in Rochester; Thursday, October 30, 2003 Parkinson's Disease To Be Targeted By Novel RNA Interference Drug Development, Alnylam Pharmaceuticals and Mayo Clinic Establish Collaboration to Advance Research Published in Science  


Copyright© 2012 Pipeline Project

All rights reserved. Revised: 01/26/12.