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This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.

update 2013-08-24: this post is deprecated, please see these two more recent posts on this subject:

Gene Therapy (from Wikipedia):

In 2003 a University of California, Los Angeles research team inserted genes into the brain using liposomes coated in a polymer called polyethylene glycol. The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the blood-brain barrier. This method has potential for treating Parkinson’s disease.[22]

RNA interference or gene silencing may be a new way to treat Huntington’s disease. Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[23]

In November 2009, the journal Science reported that researchers succeeded at halting a fatal brain disease, adrenoleukodystrophy, using a vector derived from HIV to deliver the gene for the missing enzyme.


Karine Toupet, Valérie Compan, Carole Crozet, Chantal Mourton-Gilles, Nadine Mestre-Francés, Françoise Ibos, Pierre Corbeau, Jean-Michel Verdier, Véronique Perrier, Alfred Lewin (2008). Effective Gene Therapy in a Mouse Model of Prion Diseases PLoS ONE, 3 (7), 0- DOI: 10.1371/journal.pone.0002773

Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy  approaches. Here, we used lentiviral gene transfer to deliver PrPQ167R virions possessing anti-prion properties to analyse their efficiency in vivo. Since treatment for prion diseases is initiated belatedly in human patients, we focused on the development of a curative therapeutic protocol targeting the late stage of the disease, either at 35 or 105 days post-infection (d.p.i.) with prions. We observed a prolongation in the lifespan of the treated mice that prompted us to develop a system of cannula implantation into the brain of prion-infected mice. Chronic injections of PrPQ167R virions were done at 80 and 95 d.p.i. After only two injections, survival of the treated mice was extended by 30 days (20%), accompanied by substantial improvement in behaviour. This delay was correlated with: (i) a strong reduction of spongiosis in the ipsilateral side of the brain by comparison with the contralateral side; and (ii) a remarkable decrease in astrocytic gliosis in the whole brain. These results suggest that chronic injections of dominant negative lentiviral vectors into the brain, may be a promising approach for a curative treatment of prion diseases.

How does the dominant negative PrPQ167R variant increase the incubation time of the disease? In vivo and in vitro studies have shown that PrPQ167R cannot itself be converted into its infectious PrPSc isoform and can also prevent the conversion of wt PrPC into wt PrPSc via a competitive interaction between PrPQ167R and PrPC for PrPSc [21][22][27]. Dominant negative inhibition in transgenic mice prolongs survival time by slowing the rate of PrPSc accumulation in infected animals [27]. We have shown here that mice treated with ΨPrPQ167R display a prolonged survival time although the PrPSc levels in terminally sick mice are not significantly reduced. By contrast to transgenic mice, the presence of substoichiometric PrPQ167R delivered by lentivirus may not be sufficient to completely block PrPSc formation.


“Gene and cell therapy for prion diseases,” Relano-Gines et al., Infect Discord Drug Targets (2009)

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal prion protein named PrP(Sc). PrP(Sc) results from the post-translational conformational modification of the host-encoded protein PrP(C). To date there is no treatment for this inexorably fatal disease. Hence, a major focus of research consists in the identification of new molecules that could interfere with in vivo prion propagation. Promising therapeutic approaches to block the production of PrP(Sc) are based on PrP RNA interference, passive or active immunization, dominant negative inhibition of PrP(Sc) formation, as well as inhibition of interactions between PrP(Sc) and other cofactors. Although these anti-prion molecules can be directly administered in vivo, the process to produce and purify them in high quantity is often challenging and expensive. An alternative strategy consists in the development of gene therapy systems of delivery. Importantly, the diagnosis of prion disease in humans remains difficult and often leaves a short therapeutic window after the appearance of the first clinical signs. As serious damages to the brain generally occur before clinical symptoms manifest, an ideal therapeutic strategy must target not only the formation of toxic aggregates, but also the brain destruction already incurred. This could be achieved by combining gene therapy with cell therapy. In this review we have chosen to highlight  the multiple targets and potential gene or cell replacement therapeutic approaches. This review also presents the evidence for the transplantation of stem cells as well as the combination of cell and gene therapy as promising strategies against prion diseases.


“Vaccination via gene therapy for prion diseases?  Early results show promise,” Robinson, Neurology Today (2007)

Dr. Federoff’s approach instead relies on supplying a gene for a modified antibody. The gene encodes a human single chain fragment variable (SCFV) antibody, akin to the tip of one arm of a standard immunoglobulin molecule. The molecule is small by protein standards, and lacks a complement activation region, reducing the likelihood of stimulating an unwanted immune reaction.

SCFV antibodies were developed by a combinatorial process, and selected for maximum binding to normal prion protein. The winner was an antibody called D18. We know exactly where D18 binds, Dr. Federoff said. It is to the outlying loop of PrPc, occluding the ability of PrPsc to bind to PrPc.

The AAV vector was stereotactically delivered into the brains of mice, followed by infection with the scrapie protein. After being taken up by the targeted neurons, the gene produced antibodies, which the cells secreted, spreading the protective effect beyond the transduced cells. It’s an important therapeutic point that if you have a secreted gene product, one can target a much smaller set of cells with the gene, and still have a much larger effect, Dr. Federoff said.

With the protection of this prophylactic administration, treated mice lost less motor control and lived 35 percent longer than untreated mice, and analysis showed there was considerably less scrapie burden in the brain.

We are now exploring, with peripheral vaccination in other animal models, whether we can treat established disease, Dr. Federoff said. This will be required before any kind of clinical trial is planned, he said.

Dr. Federoff noted the risks and benefits of this technique must also be evaluated against other approaches, such as using small molecules to block the interaction between proteins. Investigations by other groups have indicated this may be possible. The potential to treat a brain disorder without a systemic effect, I think, still remains one of the most attractive features of CNS gene therapy, he said.

Our best understanding is that this therapy is working in a purely stoichiometric fashion, he said, with a direct and prolonged interaction between a single normal protein and a single antibody. Therefore, you might predict that if you can increase the mass of molecules you deliver, you might be able to cure the disease. That study is ongoing, with repeated dosing, but the problem is that the cells we’ve targeted are neurons. It might be preferable to target unaffected cells, such as glia, using a different AAV serotype.


Lentivirus (from Wikipedia)

Lentivirus is primarily a research tool used to introduce a gene product into in vitro systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference technology in high-throughput formats.[1] The expression of short-hairpin RNA (shRNA) reduces the expression of a specific gene, thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can be a precursor to the development of novel drugs which aim to block a gene-product to treat diseases.

Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophilia.[2] Lentiviral infection have advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity. Lentiviruses have also been successfully used for transfection of diabetic mice with the gene encoding PDGF (platelet-derived growth factor),[3] a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studiesGammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.[4]