Curr Gene Ther. 2007 Aug;7(4):239-48.
Federici T, Boulis N.
Cleveland Clinic, Department of Neurosciences and Center for Neurological Restoration, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Peripheral nerve diseases, also known as peripheral neuropathies, affect 15-20 million of Americans and diabetic neuropathy is the most common condition. Currently, the treatment of peripheral neuropathies is more focused on managing pain rather than providing permissive conditions for regeneration. Despite advances in microsurgical techniques, including nerve grafting and reanastomosis, axonal regeneration after peripheral nerve injury remains suboptimal. Also, no satisfactory treatments are available at this time for peripheral neurodegeneration occurring in motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).
Peripheral nerves have the inherent capacity of regeneration. Gene therapy strategies focused on neuroprotection may help optimizing axonal regrowth. A better understanding of the cellular and molecular events involved in axonal degeneration and regeneration have helped researchers to identify targets for intervention. This review summarizes the current state on the clinical experience as well as gene therapy strategies for peripheral neuropathies, including MND, peripheral nerve injury, neuropathic pain, and diabetic neuropathy.

Researchers from the University of Pittsburgh School of Medicine report that they have successfully used gene therapy to block the pain response in an animal model of neuropathic pain, a type of chronic pain in people for which there are few effective treatments. These findings are being presented at the 10th annual meeting of the American Society of Gene Therapy, being held May 30 to June 3 at the Washington State Convention & Trade Center, Seattle.

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(From Science Daily.) A new agent, called “Zorro-LNA,” appears to have the potential to stop genetic disorders in their tracks. In a study to appear in the June 2007 issue of The Federation of American Societies for Experimental Biology Journal, researchers from the Karolinska Institute in Stockholm, Sweden, describe how they developed Zorro-LNA to bind with both strands of a gene’s DNA simultaneously, effectively disabling that gene.
This development has clinical implications for virtually every human condition caused by or worsened by dominant defective genes. Examples include: Huntington’s disease, familial high cholesterol, polycystic kidney disease, some instances of glaucoma and colorectal cancer, and neurofibromatosis, among others.
“Zorro-LNA is a new substance that targets DNA and turns off genes,” said co-author Edvard Smith of the Karolinska Institute in Sweden. “It has the potential of becoming a new drug for the treatment of human genetic disease.”
The findings described in this article significantly raise the possibility that new therapies could arise where defective DNA is deactivated more completely and more thoroughly than ever before. For instance, Zorro-LNA could be used in combination with “RNA interference” (RNAi). Like Zorro-LNA, RNAi has the ability to deactivate genes, but does so by degrading the gene’s RNA. In addition, Zorro-LNA could be used to deactivate certain genes in stem cells, which could eventually lead to the development of new cells, tissues, or organs. (The discovery of RNAi was recognized by a Nobel Prize award in 2006 to two American scientists.)
“This is a major development in the treatment not only of genetic diseases, but also of acquired diseases when microbes or toxins cause genes to go awry” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “One might say these researchers have found a gene-hunter’s Holy Grail for which scientists have been hunting for many years. Zorro-LNA should give us a new, safe way of blocking the effects of errors in our genetic repertoire.”

For more than two decades, gene delivery has been accomplished by using engineered viruses as a vehicle to get into diseased cells and 70 percent of clinical trials worldwide continue to use this method. But, the viruses used for gene delivery occasionally evoke severe immune responses, so scientists continue to search for non-viral delivery vehicles.
Lipid DNA complexes are attracting increasing attention as non-viral DNA delivery vehicles. They have been described as one of the “hottest new technologies” for gene therapy, accounting for nearly 10 percent of ongoing clinical trials.

Elena Rugarli and colleagues from the National Neurological Institute in Milan have used gene therapy to save sensory and skeletal muscle nerve fibers from degeneration in mice with hereditary spastic paraplegia (HSP).
This strategy, reported online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, holds promise for many other disorders characterized by nerve degeneration due to loss of function of a known gene. [Read more]

Scientists have used silica nanoparticles loaded with DNA to deliver genes safely into mouse brains, a technique that could lead to gene therapies able to repair cells more safely and effectively than current methods, which rely on viral vectors.
Gene therapy seeks to transport genes into the body to treat disorders such as sickle cell anemia, cystic fibrosis, muscular dystrophy and hemophilia by supplementing unhealthy mutant genes with therapeutic proteins. With conventional viral-vector gene therapy, the body’s immune system often reacts and seeks to destroy the transported genes, rendering them ineffective. Moreover, the viral carriers may damage chromosomes when they insert genes.

Scientists are closing in on techniques that could let them safely repair almost any defective gene in a patient, opening the door for the first time to treatments for a range of genetic disorders that are now considered incurable.
The breakthrough, announced in the journal Nature in June, relies on so-called zinc fingers, named after wispy amino acid protuberances that emanate from a single zinc ion. When inserted into human cells, the fingers automatically bind to miscoded strands of DNA, spurring the body’s innate repair mechanism to recode the problem area with the correct gene sequence. [Wired]

A revolutionary treatment could provide the solution to many life-threatening, inherited diseases

Push to the back of your mind all the recent research identifying genes associated with disease. This landmark research is about actually re-writing genes. It opens up the prospect of making permanent repairs to any gene that is causing a disease or disability.
The new technique, dubbed “gene editing”, overcomes many of the problems associated with current techniques of gene therapy by harnessing the DNA’s own repair system to correct the fault in the gene. The key is something called zinc finger proteins. Remember the name — you’ll be hearing a lot more about them.

Read the full article.

A gene therapy trial patient developed leukemia as a direct consequence of the experimental treatment, and the study was halted immediately. Apparently the altered gene inserted itself next to an oncogene, and when the two-and-a-half year old boy developed a case of the chicken pox, the gene was activated and he began to produce excess quantities of white blood cells. The boy is responding well to chemotherapy, and trials will continue because some people will undoubtedly die without gene therapy treatment. I believe this just illustrates the fact that every new treatment is bound to have some risks, especially when we don’t yet understand exactly how the human genome works.