Degenerative Erkrankungen des Bewegungsapparates insbesondere der Wirbelsäule stellen den häufigsten Erkrankungstyp des älteren Menschen dar. Nach Untersuchungen des "National Center for Health Statistics" leiden annähernd 500 von 1000 Personen über 65 Jahren an degenerativen Erkrankungen. Die Zahlen dürften für die Bundesrepublik ähnlich hoch liegen.Degenerative diseases of the musculoskeletal systemcouncils especially the spine represent themost common type of disease in the elderlyAccording to investigations by the "National Center forHealth Statistics "affects approximately 500 out of 1000People over 65 years of age with degenerative diseasekungen. The numbers are likely for the Federal Republicare similarly high.
Bandscheibe und Wirbelsäulengelenke sind Organe, die mit Medikamenten schwierig zu erreichen sind. Intravenöse und orale Verabreichungen von Medikamenten mit potentiell analgetischer und arthrosehemmender Wirkung erreichen nur bedingt den Bandscheibenraum bzw. den Innenraum arthrotisch veränderter kleinen Wirbelgelenke, da die entsprechenden Strukturen verminderten Anschluß an das vaskuläre System haben. Vermindert werden die Gewebespiegel therapeutischer Substanzen in der Bandscheibe und den kleinen Wirbelgelenke außerdem durch die passive Diffusion von den Kapillaren in die Bandscheibe bzw. den Gelenkinnenraum. Dabei gilt, daß je größer das verabreichte Molekül ist, um so niedriger die Diffusion in diese Zielgebiete ist. Der Zugang von großen therapeutisch wirksamen Molekülen (z. B. Proteinen) in diese Areale ist damit wesentlich erschwert.The intervertebral disc and spinal joints are orgne that difficult to achieve with medicationare. Intravenous and oral administrations ofDrugs with potentially analgesic and arAchieve throses only limitedthe intervertebral disc space or the interior arthrotically modified small vertebral joints, because thecorresponding structures reduced connectionto the vascular system. Diminishes whothe tissue level of therapeutic substancezen in the intervertebral disc and the small vertebraealso steer through the passive diffusion ofthe capillaries in the intervertebral disc or the gelsinterior. It applies that the larger therich molecule is, the lower the diffusion inthis is target areas. The access of great therapeutically active molecules (e.g. proteins) inthese areas are therefore considerably more difficult.
Obwohl intraartikuläre und intradiskale Injektionen einen direkten Zugang von Medikamenten ermöglichen und damit die genannten Probleme umgehen, haben therapeutisch interessante Substanzen (z. B. IL-1 Antagonisten) eine kurze Halbwertzeit im Gewebe. Wegen der Chronizität sind viele Injektionen erforderlich. Wiederholte Injektionen bergen das Risiko der bakteriellen Infektion.Although intra-articular and intradiscal injectionsdirect access to medicationand thus deal with the problems mentioned,have therapeutically interesting substances (e.g.IL-1 antagonists) have a short half-life in Geweave. Because of the chronicity there are many injectionsrequired. Repeated injections hide thatRisk of bacterial infection.
Bisher ist es daher üblich, systemisch mit hohen Gewebespiegeln zu therapieren, um so eine effekti ve therapeutische Dosis in der Zielstruktur (Bandscheibe u. Wirbelgelenke) zu erlangen. Allgemeine Nebenwirkungen werden damit begünstigt.So far, it has therefore been common to use systemic highTo treat tissue levels in order to be effective ve therapeutic dose in the target structure (volumedisk u. Vertebral joints). GeneralThis favors side effects.
Das gleiche gilt auch für die Therapie von Nervenerkrankungen. Bedingt durch die Ausbildung der Bluthirnschranke sind Anwendungen großer therap. Proteine sehr erschwert.The same applies to the therapy of nervesdiseases. Due to the training ofBlood brain barrier are applications of great therap.Proteins very difficult.
Das grundlegende therapeutische Konzept des molekularbiologischen Ansatzes des Patentes liegt darin, den Gencode der Chondrozyten, Fibroblasten und Nervenzellen der Wirbelsäule so zu verändern, daß diese Zellen Proteine mit therapeutischen Eigenschaften synthetisieren (Beispiel WirbelgelenkeAbb. 1). Im Falle der Expression der Gene synthetisieren und sezernieren Chondrozyten, Neurone und Fibroblasten antiinflammatorische und analgetische Moleküle in den Bandscheibenraum oder in den Gelenkinnenraum.The basic therapeutic concept of the molecular biological approach of the patent is to change the gene code of the chondrocytes, fibroblasts and nerve cells of the spine so that these cells synthesize proteins with therapeutic properties (example vertebral gels keFig. 1). If the genes are expressed, chondrocytes, neurons and fibroblasts synthesize and secrete anti-inflammatory and analgesic molecules into the intervertebral disc space or into the interior of the joint.
Durch diesen Zugang kann das Repertoire der z.Z. therapeutisch genutzten relativ kleinen Moleküle auf neue größere Proteine ausgeweitet werden. Dies wäre von Vorteil, da einige Proteine (z. B. Hemmstoffe der Zytokine) Eigenschaften aufweisen, die sie für die o.g. Erkrankungen favorisieren. Wegen ihrer Größe, schlechten Penetration in die bradytrophen Gewebe und wegen ihrer physiologischen Instabilität wurden bisher solche Substanzen auf ihren praktischen therapeutischen Nutzen nur wenig untersucht.Through this access, the repertoire of the currentlyrelatively small molecules used for therapeutic purposesnew larger proteins are being expanded. Thiswould be advantageous because some proteins (e.g. inhibitorsubstances of the cytokines) have properties thatthem for the above Favor diseases. Because oftheir size, poor penetration into the bradytrophen tissue and because of their physiological inSo far such substances have been found on ihlittle practical therapeutic benefitexamined.
Der jetzige wissenschaftliche Stand in der Diskussion der biochemischen Verursachung degenerativer Erkrankungen des Bewegungsapparates läßt den Schluß zu, daß Interleukin-1 (IL-1) der entscheidende Mediator der pathologischen Veränderungen ist (3, 10). IL-1 ruft synoviale Entzündung, Knorpelverlust und Knochenresorption hervor (2, 5, 6, 7). In tierexperimentellen Untersuchungen konnte gezeigt werden, daß Antikörper gegen IL-1 den Ausprägungsgrad der experimentellen Arthritis wesentlich abschwächen (10). Auch erste klinische Untersuchungen zur Behandlung der Arthrose mit IL-1 Rezeptorantagonisten (IRAP) erscheinen vielversprechend (1, 4). Im Zusammenhang degenerativer Wirbelsäulenerkrankungen ist das Zusammenspiel der Interleukine mit dem peripheren Nervensystem von besonderem Interesse (9).The current state of science in the discussion of biochemical causation degenerativer diseases of the musculoskeletal systemconcluded that interleukin-1 (IL-1) der entoutgoing mediator of pathological changesis (3, 10). IL-1 causes synovial inflammation,Cartilage loss and bone resorption (2, 5,6, 7). In animal experiments,are shown that antibodies against IL-1 denDegree of expression of experimental arthritis weweaken considerably (10). Also first clinicalStudies on the treatment of arthrosis with IL-1 receptor antagonists (IRAP) appear a lotpromising (1, 4). In the context of degenerative diseases of the spine is togetherInterleukins play with the peripheral nerve systemstem of special interest (9).
Mit Blick auf diesen Hintergrund wird vom Erfinder vorgeschlagen, ein Gentransfersystem bei degenerativen Wirbelsäulenerkrankungen und degenerativen Nervenerkrankungen einzuführen,das insbesondere die Wirkungen von IL-1 mit einem neuartigen Gentransfersystem anatagonisiert. Dabei konnte entweder das Gen für IRAP oder für einen IL-1 Rezeptor in Fibroblasten, Chondrozyten und Neuronen codiert werden. Mit diesem gentechnischen Transfersystem lassen sich aber auch zusätzliche oder alternative Gene für andere therapeutische Proteine in die Wirbelgelenke, Nerven oder in den Bandscheibenraum einbringen.With this in mind, the inventorproposed a gene transfer system at degeneratative spinal diseases and degeneratito introduce venous nerve disorders, especiallyespecially the effects of IL-1 with a novelanatagonized gene transfer system. Herecould either be the gene for IRAP or for oneIL-1 receptor in fibroblasts, chondrocytes andNeurons are encoded. With this gentechniHowever, transfer systems can also be usedadditional or alternative genes for other therapeutic proteins in the vertebral joints, nervesor insert into the intervertebral disc space.
2 verschiedene Systeme werden vom Erfinder vorgeschlagen(Abb. 2).The inventor proposed 2 different systems (Fig. 2).
Der direkte Zugang wird durch Injektion eines Vektors in die kleinen Wirbelgelenke, in die Bandscheibe oder in den peripheren Nerven möglich, der Fibroblasten, Chondrozyten und Nervenzellen in situ überträgt (linke SeiteAbb. 2).Direct access is possible by injecting a vector into the small vertebral joints, into the intervertebral disc or into the peripheral nerves, which transmit fibroblasts, chondrocytes and nerve cells in situ (left sideFig. 2).
Beim indirekten Zugang wird Bandscheibengewebe, Fibroblasten und Chondrozyten der kleinen Wirbelgelenke oder Nerv entnommen, diese Zellen in vitro verändert und in das Entnahmegebiet retransplantiert (rechte SeiteAbb. 2).With indirect access, intervertebral disc tissue, fibroblasts and chondrocytes are removed from the small vertebral joints or nerve, these cells are changed in vitro and retransplanted into the removal area (right sideFig. 2).
Mit Hinblick auf die Entwicklung in der Endoskopie erscheint der indirekte Zugang für einen chirurgisch klinischen Einsatz besonders elegant, während der direkte Zugang technisch einfacher durchzuführen ist und eine allgemeine klinische Anwen dung damit erleichtert wird.With regard to the development in endoscopyindirect access for a surgeon appearsclinically particularly elegant, wuhrend the direct access technically easieris a general clinical application This will make it easier.
Der direkte Zugang wird aber durch die Unfähigkeit des retroviralen Vektors erschwert, ruhende Zellen in situ zu infizieren, da Retroviren Zellteilung zur Infektion benötigen. Allerdings kann die Zellteilung durch Entzündung, Verletzung oder partielle Gewebeentnahme selbst angeregt werden. Andere Vektoren (z. B. Adenoviren, Adeno-assoziierte Viren oder Herpesviren) infizieren auch nicht teilende Zellen, so daß diese Vektoren die vorgenannten Probleme umgehen könnten.However, direct access is due to inabilityof the retroviral vector complicates resting cellsto be infected in situ, since retroviruses cell division to Inneed a fitting. However, cell division candue to inflammation, injury or partial tissuebe stimulated yourself. Other Vekgates (e.g. adenoviruses, adeno-associated virusesor herpes viruses) also infect non-dividing cellslen, so that these vectors the aforementioned Procould handle bleme.
Beim jetzigen Stand der Entwicklung ist zu erwarten, daß der indirekte Zugang als effektiver anzusehen ist, da die Kotransduktion eines selektiven Markers eine Identifikation teilender Zellen ermöglicht.At the current stage of development is to be expectedthat indirect access should be viewed as more effectivehen, since the co-transduction of a selective Markers enables identification of dividing cells.
Nach Entnahme der Fibroblasten, Chondrozyten und Nerven aus den kleinen Wirbelgelenken, der Bandscheibe und dem Nervenkanal im Tierexperiment wurden die angelegten Zellkulturen mit einem Retrovirus infiziert (BAG-Virus oder MFGLac-Z Virus) der Marker Gene für B-Galactosidase (lac Z) enthält und gegenüber dem Neomycin Analog (G 418 neo+) resistent ist.After removal of the fibroblasts, chondrocytes andNerves from the small vertebral joints, the banddisc and the nerve canal in animal experimentsthe created cell cultures with a Retrovirus infected (BAG virus or MFGLac-Z virus)the marker contains genes for B-galactosidase (lac Z)and compared to the neomycin analog (G 418neo +) is resistant.
Diese neo-selektierten Zellen (Menge 106) wurden in den ursprünglichen Gewebebereich (Bandscheibe, kleine Wirbelgelenke und Nerv) retransplantiert, um die Persistenz und Expression dieser Ge ne in ihrer natürlichen Umgebung in vivo zu untersuchen.These neo-selected cells (amount 106 ) were retransplanted into the original tissue area (intervertebral disc, small vertebral joints and nerve) in order to investigate the persistence and expression of these genes in their natural environment in vivo.
12 Wochen nach Transplantation (s.Abb. 3 Histologie) konnte ein Überleben dieser gentechnisch veränderten Zellen in ihrer natürlichen Umgebung beobachtet werden, erkennbar an der dunkelblauen Färbung der Zellen. Es zeigte sich außerdem eine regelrechte Kolonisation. Aus dem dann wieder entnommenen Gewebe konnten diese veränderten Zellen in vitro erneut untersucht werden. Eine Abstoßungsreaktion zeigte sich nicht. Die Experimente zeigen eindeutig, daß ein Marker-Gen in diese Zellen eingebracht werden kann, das sich in situ exprimieren kann.12 weeks after transplantation (seeFig. 3 histology), the survival of these genetically modified cells in their natural environment could be observed, recognizable by the dark blue color of the cells. There was also a real colonization. These modified cells could be examined again in vitro from the tissue then removed. There was no rejection reaction. The experiments clearly show that a marker gene can be introduced into these cells that can be expressed in situ.
Außerdem gelang es bei Fibroblasten, Chondrozyten und Neuronen den Gen-Code für einen Interleukin-1 Rezeptorantagonisten in einen Retrovirus zu inkorporieren. Die Zellen, die mit diesem Virus infiziert wurden, waren in der Lage, Interleukin-1 Rezeptor Antagonisten zu produzieren.In addition, fibroblasts and chondrocytes were successfuland neurons the gene code for an interleukin1 receptor antagonists into a retroviruscorporation. The cells that infi with this viruswere able to interleukin-1 Reto produce zeptor antagonists.
Durch die gentechnisch mögliche Veränderung der Eigenschaften der Fibroblasten, Nervenzellen und Chondrozyten ergibt sich eine neuartige Strategie in der Behandlung schmerzhafter degenerativer Erkrankungen der Bandscheibe (Abb. 5), des Nerven (Abb. 4) und der kleinen Wirbelgelenke (Abb. 5).The genetically engineered changes in the properties of the fibroblasts, nerve cells and chondrocytes result in a new strategy in the treatment of painful degenerative diseases of the intervertebral disc (Fig. 5), the nerve (Fig. 4) and the small vertebral joints (Fig. 5).
Beim jetzigen Stand müssen die beschriebenen Verfahren verfeinert, ausgeweitet und auf ihre Sicherheit in größeren Serien untersucht werden.At the current status the describedProcess refined, expanded and based on your Sisafety in larger series.
Besonders interessant erscheint therapeutisch die Möglichkeit, Gene mit antagonisierender Wirkung von IL-1 zu transduzieren.Therapeutically, this seems particularly interestingPossibility of genes with antagonizing effectsto transduce from IL-1.
Die o.g. gentechnologischen Verfahren in Verbindung mit Transplantationstechniken aus der Endoskopie (z. B. transarthroskopische Synovektomie und Diskektomie) werden einen innovativen Schub in der Behandlung dieser Erkrankungen erwarten lassen.The above genetic engineering processes in Verbinwith transplantation techniques from Endoscopia (e.g. transarthroscopic synovectomyand discectomy) will be an innovative boostexpect in the treatment of these diseasesto let.
Da es sich bei dem Patentgegenstand prinzipiell um eine somatische Gentherapie handelt, ist ein Verstoß gegen ethische Normen nicht gegeben.Since the subject matter of the patent is in principlesomatic gene therapy is a verdoes not violate ethical norms.
Abb. 1 Das grundlegende therapeutische Konzept des molekularbiologischen Ansatzes liegt darin, den Gencode der Chondrozyten und der Fibroblasten der kleinen Wirbelgelenke und der Bandscheibe so zu verändern, daß diese Zellen Proteine mit therapeutischen Eigenschaften synthetisieren. Im Falle der Expression der Gene synthetisieren und sezernieren Chondrozyten und Fibroblasten (wie hier dargestellt) antiinflammatorische und analgetische Moleküle in den Gelenkinnenraum.Fig. 1 The basic therapeutic concept of the molecular biological approach is to change the gene code of the chondrocytes and the fibroblasts of the small vertebral joints and the intervertebral disc so that these cells synthesize proteins with therapeutic properties. If the genes are expressed, chondrocytes and fi broblasts (as shown here) synthesize and secrete anti-inflammatory and analgesic molecules into the interior of the joint.
Abb. 2 direkter und indirekter Zugang am Beispiel der kleinen Wirbelgelenke.Fig. 2 direct and indirect access using the example of the small vertebral joints.
Der direkte Zugang wird durch Injektion eines Vektors in die kleinen Wirbelgelenke, in die Bandscheibe oder in den peripheren Nerven möglich, der Fibroblasten, Chondrozyten und Nervenzellen in situ überträgt (linke SeiteAbb. 2).Direct access is possible by injecting a vector into the small vertebral joints, into the intervertebral disc or into the peripheral nerves, which transmits fibroblasts, chondrocytes and nerve cells in situ (left sideFig. 2).
Beim indirekten Zugang wird Bandscheibengewebe, Fibroblasten und Chondrozyten der kleinen Wirbelgelenke oder Nerv entnommen, diese Zellen in vitro verändert und in das Entnahmegebiet retransplantiert (rechte SeiteAbb. 2).With indirect access, intervertebral disc tissue, fibroblasts and chondrocytes are removed from the small vertebral joints or nerve, these cells are changed in vitro and retransplanted into the removal area (right sideFig. 2).
Abb. 3 (Histologie): Histologische Darstellung von Fibroblasten der Bandscheibe des Kaninchen nach Transplantation gentechnisch veränderter Zellen. Die dunkel gefärbten Gewebeanteile entsprechen Fibroblasten, die zuvor außerhalb des Kniegelenkes gentechnisch verändert und retransplantiert wurden.Fig. 3 (histology): histological representation of fibroblasts of the rabbit intervertebral disc after transplantation of genetically modified cells. The dark-colored parts of the tissue correspond to fibroblasts that had previously been genetically modified and retransplanted outside the knee joint.
12 Wochen nach Transplantation (s.Abb. 3 Histologie) konnte ein Überleben dieser gentechnisch veränderten Zellen in ihrer natürlichen Umgebung beobachtet werden, erkennbar an der dunkelblauen Färbung der Zellen. Es zeigte sich außerdem eine regelrechte Kolonisation. Aus dem dann wieder entnommenen Gewebe konnten diese veränderten Zellen in vitro erneut untersucht werden. Eine Abstoßungsreaktion zeigte sich nicht. Die Experimente zeigen eindeutig, daß ein Marker-Gen in diese Zellen eingebracht werden kann, das sich in situ exprimieren kann.A survival of these genetically modified cells in their natural environment could be observed 12 weeks after the transplantation (seeFig. 3 histology), recognizable by the dark blue color of the cells. There was also regular colonization. These modified cells could be examined again in vitro from the tissue then removed. There was no rejection reaction. The experiments clearly show that a marker gene can be introduced into these cells that can be expressed in situ.
Abb. 4 Nerv: Anwendung der Erfindung bei Erkrankungen des Nerven. Therapeutische Gene werden in Makrophagen oder in Fibroblasten eingebracht, die dann therapeutische Proteine exprimieren.Fig. 4 Nerve: application of the invention to diseases of the nerve. Therapeutic genes are introduced into macrophages or into fibroblasts, which then express therapeutic proteins.
Abb. 5 Wirbelsäule: Bildliche Darstellung der Anwendung der Erfindung, Möglichkeiten des Gentransfers an der Wirbelsäule (s. Text).Fig. 5 Spine: Pictorial representation of the application of the invention, possibilities of gene transfer to the spine (see text).
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| Application Number | Priority Date | Filing Date | Title |
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| DE19924219626DE4219626A1 (en) | 1992-06-16 | 1992-06-16 | Incorporating therapeutic gene via vector into body cells - in=vivo or in vitro, for subsequent expression and secretion of active protein, partic. for treating degenerative diseases of spine and nerves |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19924219626DE4219626A1 (en) | 1992-06-16 | 1992-06-16 | Incorporating therapeutic gene via vector into body cells - in=vivo or in vitro, for subsequent expression and secretion of active protein, partic. for treating degenerative diseases of spine and nerves |
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| DE4219626A1true DE4219626A1 (en) | 1993-12-23 |
| Application Number | Title | Priority Date | Filing Date |
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| DE19924219626CeasedDE4219626A1 (en) | 1992-06-16 | 1992-06-16 | Incorporating therapeutic gene via vector into body cells - in=vivo or in vitro, for subsequent expression and secretion of active protein, partic. for treating degenerative diseases of spine and nerves |
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| Date | Code | Title | Description |
|---|---|---|---|
| ON | Later submitted papers | ||
| 8110 | Request for examination paragraph 44 | ||
| 8181 | Inventor (new situation) | Free format text:ERFINDER WIRD SPAETER GENANNT WERDEN | |
| 8181 | Inventor (new situation) | Free format text:ERFINDER IST ANMELDER | |
| 8131 | Rejection |