Method for stimulating neurogeneration by genetic make-ups

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gene therapy. What is proposed for consideration is a method for stimulating spinal regeneration by the introduction into an involved area of a vector on the basis of two-cartridge plasmid pBud-VEGF-FGF2 simultaneously expressing the combination of two cloned genes of neurotrophic and angiogenic human factors VEGF and FGF2.

EFFECT: use of the invention provides more effective spinal functional recovery that can find further application in treating the patients with traumatic spinal injuries.

3 cl, 3 ex

 

The invention relates to medicine, in particular to methods of treating spinal cord injuries by introducing into the area of damage to the genes in the form of plasmid vectors expressing neurotrophic factors, and can be used in trauma centers and neurology.

Spinal cord injury remains one of the pressing issues of modern medicine. Its consequences are flaccid or spastic paralysis, paresis of the limbs and dysfunction of the pelvic organs. Over the past twenty years conducted a large number of studies on many aspects of the pathophysiology and pathology of spinal cord injury: inflammatory response, glial reaction, apoptosis, ischemia, recovery of functional activity. It was found that traumatic damage to the spinal cord causes a complex pathological changes, including death of neurons and glial cells, degeneration of nerve fibers, demyelination, activation of microglia and macrophages. These violations are the cause of sustainable functional deficit.

One of the promising approaches to the treatment of spinal cord injuries is gene therapy. There is a method of delivery of the cloned genes in the area of corruption with the help of cell carriers. For this purpose, use of embryonic and hematopoietic stem cells [see McDonld J.W. Repairing the damaged spinal cord: from stem cells to activity-based restoration therapies / J.W. McDonald // Clinical neurosurgeru. - 2004. - Vol.No. 51. - P.1-21], neural stem cells, blood cells of the umbilical cord, Schwann cells [see Survival, integration and axon growth support of glia transplantation into the chronically contused spinal cord / D.J. Barakat [et all] // Cell transplantation. - 2005. - Vol.No. 14. - P.225-240]. However, the expected increase in efficiency in the treatment of the consequences of a severe spinal cord injury has not been reached, there are certain disadvantages to these methods. Thus, when the delivery of therapeutic genes at the cellular carriers, there is a high probability of cell transformation in tumor and contamination by infectious agents during manipulation ex vivo.

Of the investigated prior art method of stimulating post-traumatic regeneration of the spinal cord with the help of delivery in the area of corruption viral vectors containing, in most cases, the genes for neurotrophic factors. Significant disadvantages of the use of viral vectors are short-term transgene expression, unwanted interaction with the immune and humoral systems, as well as complications during the initial infection. The use of retroviruses for gene therapy of neurodegenerative diseases in animal experiments it was quite effective. However, begun clinical trials are not the first who or positive effect [see Dawbarn D. Neurotrophins and neurodegeneration / D. Dawbarn, S.J. Allen // Neuropathology and applied neurobiology. - 2003. - Vol.No. 29 (3). - P.211-230].

Neurotrophic factors support the survival of neurons and stimulate their formation processes [see Lu P. Growth factors and combinatorial therapies for CNS regeneration / P.Lu, M.H.Tuszynski // Experimental neurology. - 2008. - Vol. No. 209. - P.313-320]. Their introduction in the area of traumatic injury of the spinal cord inhibits the process of secondary degeneration and helps restore nerve connections [see Thuret S. Therapeutic interventions after spinal cord injury / S. Thuret, L.D.F. Moon, F.H. Gage // Nature. - 2006. - Vol.No. 7. - P.628-663]. However, with the direct delivery of neurotrophic factors in the injury area, the effect is very short, due to rapid cleavage by enzymes of the body by proteases. Therefore, to prolong the actions necessary to introduce genes for neurotrophic factors. Their direct introduction into the area of spinal cord injury is considered to be one of the promising methods of stimulating regeneration.

When spinal trauma to stimulate the regeneration of known application of the following neurotrophic factors: VEGF, FGF2, NT3, GDNF, BDNF. When using each of them separately receive some positive results, but it does not provide significant improvement of the structure and function of the spinal cord.

The closest to the achieved result is SP is a way of introducing into the area of damaged plasmid vector based on the two-cassette plasmid, expressing a combination of genes l-2 and LacZ, which are not derived neurotrophic factors [see DNA plasmid that codes for human BcL-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats / K. Takanashi [et all] // The journal of comparative neurology. - 1999. - Vol.No. 171. - P.159-171]. In this work, on the model of transection of the spinal cord of rats with only one hand (hemisection) at the level of the lower thoracic (T8) investigated the effect of injection into the area of damaged plasmid DNA with two genes, genome protivopolozhnogo protein Bcl-2, inhibiting cell death, and the reporter gene LacZ bacterial galactosidase, which serves as a label for identification of transfected (which introduced genes) cells of the recipient and does not affect the survival of these cells. Both genes introduced into the site of injury are not derived neurotrophic factors. In the mentioned work the plasmid vector was administered in combination with cationic lipids in the spinal cord in the area adjacent to the area of traumatic injury. therapeutic dose was 20-50 μg of plasmid vector per animal. Two months after the injury and the introduction of genes number of surviving neurons in the motor nuclei Clark-side operations increased significantly.

To promote post-traumatic regeneration of the spinal cord delivery method combination of genes derived neurotrophic the actors by direct gene therapy using plasmid vectors are not investigated and are not applied (not known from the investigated prior art).

The essence of the claimed technical solution is to promote post-traumatic regeneration of the spinal cord by delivery to the site of injury plasmid vector, characterized in that the stimulation of regeneration of the spinal cord is carried out by direct injection of plasmid vector based on the two-cassette plasmid pBud SE expressing a combination of cloned genes for neurotrophic factors (pBud-VEGF-FGF2). The claimed method of stimulation according to claim 1, characterized by the fact that at the same time using two gene-derived neurotrophic and angiogenic factors: vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). The claimed method of stimulation according to claim 1 characterized by the fact that the plasmid vector with a combination of genes vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) in a therapeutically effective dose directly administered by injection into the site of injury of the spinal cord.

Known plasmid pBud-VEGF-FGF2, simultaneously expressing both genes [see application for invention No. 2009133970, priority date 11.09.2009]. The effects of this combination of genes on the processes of post-traumatic regeneration of the spinal cord has not previously been studied and remain unexplored.

The claimed method of regeneration of the spinal cord using plasmid is the sector pBud-VEGF-FGF2 has been studied in laboratory rats and described in detail in the following examples:

Example 1

Model dosed contusion injury of the spinal cord of the rat at the level of T8 we have studied the effects of gene delivery of VEGF and FGF2 on neuroregeneration. Rats under anesthesia at the level of the eighth segment of the spinal cord after laminectomy inflicted dosed contusion injury vertically falling metal rod weighing 10 g from a height of 12.5 mm Immediately after injury Hamiltonian syringe were injected with 40 μg of plasmid vector pBud-VEGF-FGF2 in 5 μl saline into two points at a distance of 1 mm rostralnie and Caudalie from the epicenter of the injury and 0.5 mm lies lateral to the midline. Similarly, the rats of the control group were injected plasmid vector expressing the gene of the green fluorescent protein (EGFP). Animals were kept under standard conditions with free access to feed and water. The object of the study was the spinal cord isolated from animals 30 days after application contusion injury of the spinal cord.

Example 2

On cryostatic transverse sections of the spinal cord at a distance of 1.5 cm from the epicenter of the injury indirect immunoperoxidase method revealed perivascular cells with antibodies against beta-receptor platelet-derived growth factor (PDGFRbeta). Using this method, it was found that on the 30th day after the surgery with the introduction of the plasmid vector in the outer zones of the white island is estva the spinal cord at a distance of 1.5 cm from the epicenter of the injury, the number of perivascular cells, expressing beta-receptor platelet-derived growth factor (PDGFRbeta), increases on average by 54% (P<0.05) as compared with the corresponding figure in animals of the control group (similar to spinal cord injury, but without injection of genes). This indicates a strengthening of the formation of new blood vessels in the white matter of the spinal cord in the area of traumatic injury.

Example 3

To analyze the recovery of motor function used behavioral test "BBB" [see D.M. Basso A sensitive and reliable locomotor rating scale for open field testing in rats / D.M. Basso, M.S. Beattie, J.C. Bresnahan // Journal of Neurotrauma. - 1995. - Vol. No. 12. - P.1-21]. It is established that the rate of recovery of motor function (BBB) when injected into the injury area plasmid vector pBud-VEGF-FGF2 increases by 58% (P<0.05) in comparison with the corresponding figure in animals of the control group (similar to spinal cord injury, but without injection of genes).

Thus, the obtained experimental results indicate that direct delivery of a combination of therapeutic genes vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) in the area of spinal cord injury leads to a positive therapeutic effect, namely:

- the reduction of the area of destruction of gray and white matter,

- stimulates vascular the tion of brain tissue,

- supports his post-traumatic regeneration.

The claimed method, in contrast to the known world at the date of the filing of the best ways to treat spinal cord injuries, suggests a significant increase of the efficiency of recovery of the spinal cord.

In the proposed method uses gene vascular endothelial growth factor (VEGF).

He has a strong stimulating effect on the process of neovascularization, which is important to remove the effects of post-traumatic cerebral tissue. VEGF exhibits properties typical of neurotrophic factor.

PDGF-B through the receptor entrance PDGFβR stimulates differentiation pericytes from precursors expressing PDGFβR, which has a supporting effect on the process of vascularization. Registered by the applicant by day 30 of the experiment, the increase in the number of PDGFβR+cells reflects the increased vascularization of the white matter in the field of traumatic spinal cord injury. It is assumed that this effect is the result of actions taken as part of a plasmid vector genes for angiogenic factors and their expression in recipient cells in the damaged area of the spinal cord.

The second gene in the claimed combination is the gene for fibroblast growth factor 2 (FGF2) - representative CL is key collection gradients, which control the induction and specification of tissues in embryogenesis. The molecule is a growth factor that has a strong neurotrophic activity and is considered as a mandatory component in environments for directed differentiation of neural cells in vitro. Formed in the spinal cord FGF2 is required for proliferation of neural precursors, as shown in vivo and in vitro

Delivery of FGF2 in the area of spinal cord injury significantly reduces the amount of pathological cavities and promotes the preservation of the white matter. When spinal cord injury FGF2 enhances the expression of adhesion molecules L1, which supports the survival of neurons and axonogenesis, as well as the expression of glial fibrillar acidic protein (GFAP) in astrocytes [see Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury / I.Jakovcevski [et all] // Journal of Neurotrauma. - 2007. - Vol.No. 27. - P.7222-7233], but inhibits the sprouting of nerve fibers through the glial scar at the injury of the spinal cord.

An advantage of the claimed method from the known to the world at the filing date of the application is to use a plasmid vector that expresses the combination of genes of neurotrophic factors. Applying a combination of neurotrophic factors support the survival of neurons and stimulates neovascularization, called the em at the same time have a positive impact on several of the above processes with traumatic spinal cord injury.

To use the claimed method is recommended in the acute phase of traumatic injury of the spinal cord, since the applied combination of genes neurotrophic and angiogenic factors contribute to the elimination of post-traumatic ischemia tissue and supports the survival of neurons.

The claimed technical solution meets the criterion of world novelty, since the aggregate of the stated characteristics are not known from the prior art at the filing date of the application.

The claimed technical solution meets the criterion of inventive step, since it is not obvious to experts in the chosen field of medicine.

The claimed technical solution meets the criterion of industrial applicability, as tested in laboratory conditions in experimental animals that has provided the claimed technical result.

1. The way to promote post-traumatic regeneration of the spinal cord by delivery to the site of injury plasmid vector, characterized in that the stimulation of regeneration of the spinal cord is carried out by direct injection of plasmid vector based on the two-cassette plasmid pBud-VEGF-FGF2, at the same time expressing a combination of cloned genes neurotrophic and angiogenic factors VEGF and FGF2.

2. The method of stimulation according to claim 1, characterized in that simultaneously use two therapeutic gene: the gene for vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2).

3. The method of stimulation according to claim 1, characterized in that the plasmid vector with a combination of genes vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) in a therapeutically effective dose directly administered by injection into the site of injury of the spinal cord.



 

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9 cl, 2 ex, 1 tbl

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2 cl, 6 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is an adhesive composition containing donepezil and a stabiliser. The stabiliser containing one or more compounds specified in a group consisting of ascorbic acid, metal salt or ester of such, isoascorbic acid or metal salt of such, ethylene-diamine-tetraacetic acid or metal salt of such, cysteine, acetylcysteine, 2-mercaptobenzimidazole, 3(2)-tert-butyl-4-hydroxyanisol, 2,6-di-tert-butyl-4-methylphenol, tetrakis[3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)]propionate pentaerythrite, 3-mercapto-1,2-propanediol, tocopherol acetate, rutin, quercetin, hydroquinone, metal salt of hydroxymethansulphinic acid, metabisulphite metal salts, sulphite metal salt and thiosulphate metal salts; it is added to a layer of a pressure sensitive adhesive applied on at least one side of the substrate.

EFFECT: prepared high reliable and stable adhesive composition which inhibits formation of donepezil-related compounds in the layer of the pressure sensitive adhesive.

14 cl, 4 tbl

FIELD: chemistry.

SUBSTANCE: disclosed is an isolated nucleic acid which codes a KillerRed intramolecular dimer. Also disclosed is an expression cassette, a cell which produces a KillerRed intramolecular dimer, as well as an isolated protein which is a KillerRed intramolecular dimer. The protein consists of two copies of the KillerRed protein joined in tandem, exhibits monomer properties and can be used to produce chimeric proteins with a wide range of target proteins.

EFFECT: invention can be used in biomedical research.

4 cl, 2 dwg, 6 ex

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