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WO1998037900A1 - Utilisation de l'arn a la place d'une proteine, dans la production de substances bioactives ou pour la modulation de l'immunite specifique - Google Patents

Utilisation de l'arn a la place d'une proteine, dans la production de substances bioactives ou pour la modulation de l'immunite specifique Download PDF

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Publication number
WO1998037900A1
WO1998037900A1 PCT/LT1998/000001 LT9800001W WO9837900A1 WO 1998037900 A1 WO1998037900 A1 WO 1998037900A1 LT 9800001 W LT9800001 W LT 9800001W WO 9837900 A1 WO9837900 A1 WO 9837900A1
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WO
WIPO (PCT)
Prior art keywords
rna
substances
immunity
cells
protein
Prior art date
Application number
PCT/LT1998/000001
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English (en)
Inventor
Virmantas STUNZÉNAS
Original Assignee
Stunzenas Virmantas
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Stunzenas Virmantas filed Critical Stunzenas Virmantas
Priority to DE19882018T priority Critical patent/DE19882018T1/de
Priority to GB9918974A priority patent/GB2337462A/en
Priority to JP53753298A priority patent/JP2001517215A/ja
Publication of WO1998037900A1 publication Critical patent/WO1998037900A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression

Definitions

  • RNA chosen instead of a protein in production of bioactive substances or for specific immunity control
  • This invention is devoted to use of ribonucleic acids in medicinal substances including compositions, vaccines, transplants, intended for medical treatment, prophylactic treatment, cosmetic care; to injection of these substances into patient's organism.
  • RNA The ribonucleic acid
  • ribonucleic acid (hereinafter - RNA) is a monolithic non-branching biopolymer composed of ribonucleodites.
  • the RNA directly takes part in synthesis of proteins and there are three types of RNA: ribosomal RNA, transport RNA and messenger RNA.
  • the main of them is the messenger RNA (hereinafter - mRNA) which is synthesized on DNA-matrix and transfers all the information on sequence of amino acids in the protein to the place of synthesis of the protein where, based on this RNA, proteins are synthesized with help of ribosomal RNA and transport RNA (Lewin B. Genes 1983, New York; Saenger W. Principles of Nucleic Acid Structure 1984, New York, Berlin).
  • Proteins and their combinations are among the most important structural and functional elements of an organism.
  • the combinations of proteins are widely used in treatment, cosmetic care. These combinations are simply injected into patient's body. Nevertheless, even small protein molecules having molecular weight equal to 5000 or even less cause immunity reaction and production of antibodies (Frimel H., Brok I. Basics of Immunology 1986, Moscow).
  • RNAs chosen instead of proteins in production of medicinal substances is based on the fact the foreign RNA is capable to cross cell's membrane and to function as protein matrix inside the cell. So it is possible to introduce ferments, hormones, antibiotics, proteins of cell's receptors, structural proteins directly into cells of an organism. It is possible to introduce ribosomal and transport RNAs together with messenger RNA. When there is introduced RNA coding particular hormone or antibiotic, proteins of cell's receptors or structural proteins, into recipient's organism, these substances will be synthesized directly in recipient's cells.
  • Use of RNA instead of protein combinations gains an advantage over other analogues already by the fact the RNA has no immunogenic properties and therefore causes no unwanted inflammatory reactions.
  • mRNA When comparing to use of DNA in medicinal substances, use of mRNA gains an advantage by the fact the amount of mRNA in an organism can be controlled easily because mRNA doesn't make replicas of its own in absence of DNA. Additionally, there can be synthesized a protein immediately on mRNA introduced into the cell and this is impossible in a case of DNA. This property makes mRNA the more reliable regulator of amount of protein in patient's organism, when comparing to DNA.
  • RNA concentration of RNA introduced may be chosen in very wide range:
  • RNA binds to a wide range of proteins
  • problems being solved permeability of membranes of cells
  • activity of ribonucleases and other factors.
  • RNA extraction it is enough to use known and tested methods of RNA extraction, it is possible to match various bioactive substances which can exist and function in a normal way only inside a cell.
  • bioactive substances which can exist and function in a normal way only inside a cell.
  • RNA extracted isn't "adenylated"
  • mRNA protein together with mRNA coding the desired protein; without such help it wouldn't be possible to obtain optimal translation, or the protein wouldn't be active sufficiently.
  • RNAs of well-known substances are activated accordingly.
  • total RNA extracted from eukaryotic cells fissioning in culture can be used to stimulate regenerative processes in patient's damaged organs: RNA introduced will stimulate protein synthesis in cells of damaged organ and this will induce more intensive fission of these cells and synthesis of mediators.
  • RNAs characteristic to organ or tissue damaged I suppose RNAs can be used also to correct disorders of development an embryo introducing RNAs coding proteins inducing or retarding interaction, fission and specialization of cells, into organ of an embryo or its germ chosen.
  • RNAs synthesized by cancer cells in immunity cells of an organism. This can be done by introducing RNA which doesn't code protein combinations of pathogen cells or parasite organisms, into patient's organism or directly into organ damaged. The best way is to use RNA extracted from activated immunity cells, or mRNAs coding receptors of immunity cells or protein combinations activating these cells. It is possible also to use any other mRNA which after combination with ribosomes would be able to compete with mRNAs of pathogens and to retard translation of these mRNAs.
  • RNA preparations and treatment methods reduce synthesis of RNA and its total amount in the whole organism. It is expedient to supplement these preparations and treatment methods with use of RNA preparations.
  • introduction of mRNA it is possible not only to inhibit synthesis of mRNA of cancer cells in immunity cells, but also to restore synthesis of protein combinations in these cells having chosen mRNA correspondingly.
  • the other side of this method is, there will be synthesized protein combinations not suitable for needs of cancer cells and this will diminish malignancy of these cells.
  • the method of induction of immunological tolerance proposed in this invention is based on the principle, immunity cells don't stimulate immunity reactions against these protein combinations which are synthesized by them.
  • This method stipulates that prior to introduction of protein combinations into patient's organism or transplantation of tissue and organs, recipient's immunity cells shall be incubated together with RNAs which are used in synthesis of protein combinations having analogous immunogenic properties as substances being introduced or tissue and organs being transplanted.
  • Immunity cells can be incubated together with RNA in two ways: 1) to introduce RNAs directly into patient's organism (it is possible to introduce into vein or. into the place of planned surgical operation, or to use any other method known); 2) to mix cells extracted (e.g.
  • RNAs from patient's blood
  • RNAs re-introduce or introduce
  • macrophages they are the best absorbers of foreign substances and are the most important ones in primary immunity reaction
  • any other group of cells depending on problems being solved.
  • RNA coding proteins of tissue-compatibility complex When transplanting tissue, organs, there shall be used RNA coding proteins of tissue-compatibility complex, corresponding to donor's proteins and differing from recipient's ones. It is possible to produce or extract RNA coding separate proteins of tissue-compatibility complex, the needed combinations of which would be used to suppress activation of recipient's immunity cells against donor's tissue being transplanted. It would be possible to do it in simpler way, using RNA extracted from donor's tissue (e.g. blood or blood cells). Not always it is needed to use RNA coding proteins of tissue-compatibility complex: having determined in vitro what the protein combinations cause the development of immunogenic reactions, there is chosen the RNA corresponding to these proteins and intended to suppress recipient's immunity reactions against the transplant or transplant's reactions against the recipient.
  • compositions with RNA coding proteins corresponding to recipient's antigens are incubated together with tissue, organs, cells being transplanted. It is possible also to introduce into recipient's organism donor's cells together with RNAs coding proteins having properties of recipient's antigens.
  • This method of induction of tolerance can be used not only for transplantation or introduction of antigenic substances.
  • it is needed to treat barrenness and complications of pregnancy which arise because of insufficient immuno-suppressive activity of placenta it is possible to use in pharmaceutical compositions intended to suppress immunity reactions against embryo's antigens, RNAs coding proteins having analogous antigenic properties in respect of embryo's proteins causing complications.
  • the cause of barrenness is immunization against antigens of outer layer of an ovule
  • the process of auto-immunological sickness also can be controlled by means of pharmaceutical compositions in which RNA is used. Having determined which protein combinations cause production of immunoglobulins, it is needed to treat with RNA coding these immunogens and making basis to synthesize in immunity cells substances which have antigenic properties analogous to antigenic properties of patient's tissue which are the target of these auto-immunity reactions. Since auto- immunological sickness very often is caused by infectious micro-organisms, such treatment would allow to remove agents of sickness in process of treatment without suppressing general immunity of an organism.
  • RNA separated from the protein can also be a tolerogen, in some cases better results can be achieved by using RNA together with a solution of the protein coded by this RNA.
  • RNA Ribonucleic acid
  • the RNA extracted becomes several times more active when mixed with RNA of genome of plant virus. As far as I know the most suitable for this is the genome of vigna mosaic virus (Monk M. Mammalian Development. A Practical Approach. 1987, Oxford). Even more attractive is the use of recombinant RNA- viruses with inserted required RNA-sequence into their genome.
  • RNA Prior to introduction of foreign RNA it is desirable to have minimal amount of recipient's RNAs in patient's cells. It is easy to achieve when using medicine (antibiotics also will do) temporary inhibiting synthesis of RNAs. It should be done in all cases wnen there is required maximal productivity of RNA introduced. Having introduced RNA into patient's organism, there is a large probability to have this RNA destroyed by ribonucleases before this RNA reaches the place of translation. Therefore it would reasonable to introduce inhibitors of ribonucleases together with RNA. Among inhibitors the most suitable one would be the inhibitor extracted from placenta. But this inhibitor can be immunogenic one, so it would be needed to use it together with coding RNA, or when recipient's immunity is suppressed (e.g. after radiotherapy).
  • RNAs in bioactive compositions, not always it is possible to separate easily one protein-coding RNA from others, the RNA of one type from other one. Of course, it isn't needed in all cases. For example, when there are produced pharmaceutical compositions (to suppress transplant-rejection reactions) with mRNAs coding proteins of corresponding tissue-compatibility complex, there is no need to get rid of all other RNAs; they can be useful to restore regeneration functions of cells especially when antibiotics suppressing synthesis of RNAs are in use.
  • RNA existing in edged or killed pathogenic organisms can stimulate recipient's tolerance in above-described way, and greater variety of immunogenic substances (not separate proteins or their combinations) can create more stable immunity against this pathogen.
  • This method of increasing immunogenicity can be used at first in cases when inactivated pathogens are used as immunogenic substances.
  • RNA of a pathogen can be destroyed by means of UV-rays, X-rays, radio-active irradiation, or chemical substances having properties of ribonucleases. The best results would be obtained when using combinations of methods of RNAs' inactivation.
  • the final product shall be checked against some known and suitable for particular circumstances method determining remainder of RNAs.
  • RNAs directly in production of bioactive compositions, bioactive substances is as following: where to take the needed amount of RNA.
  • RNA can be extracted from donor's blood, blood cells, corresponding organs, animal's tissue, or any other living organisms used in biotechnological industry as well.
  • Contemporary biotechnology allows to cultivate microorganisms, viruses with DNA or RNA (they can be copied from RNA chosen) inserted into their genome, and these micro-organisms and viruses would constitute the basis for synthesis of RNA in plants, algae or cultures of microorganisms.
  • RNA used in all experiments was extracted from liver taken from mice done away with ether. RNA was extracted using phenol-method described in the book: Monk M. Mammalian Development. A Practical Approach. 1987, Oxford.
  • mice of CC57W line and with cancer- cells of Erhlich There were carried out experiments with mice of CC57W line and with cancer- cells of Erhlich. For each mouse there was injected under skin on shoulder-blade the amount of 0.2 ml of cancer-cell suspension taken from peritoneal cavity of one mouse. 5, 19 and 24 days later next to cancer tumour for each mouse there was injected the amount of 0.2 ml of solution having concentration of 0.03 mg/ml: RNA extracted from liver taken from the mice of CC57W or DBA line, in physiologic solution. In time of check test, for each mouse there was injected the amount of 0.2 ml of physiologic solution. On the 30-th day after injection of cancer cells all the mice were done away with ether. After autopsy cancer tumours were removed and weighted.
  • mice of DBA and BALB lines There were carried out experiments when transplanting patches of skin from a mouse belonging to one line onto a mouse belonging to other line.
  • mice of DBA and BALB lines their RNAs were used for induction of tolerance in a mouse of other line.
  • RNA extracted from the mice of CBA line One hour before transplantation, for each mouse there was injected the amount of 0.3 ml of RNA solution in physiologic solution; concentration 0.02 mg/ml. Then there was transplanted 1 cm 2 of skin taken from the tail of one mouse onto the back of other mouse having removed beforehand the patch of skin of appropriate size. All surgical operations were performed with mice put to sleep with ether.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
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  • Biochemistry (AREA)
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  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne l'utilisation d'acides ribonucléiques dans des substances médicinales, dont des compositions, des vaccins, des greffons, pour le traitement médical, prophylactique et les soins de beauté. Elle porte aussi sur l'injection de ces substances dans l'organisme d'un patient de sorte qu'il est possible d'introduire des ferments, des hormones, des antibiotiques, des protéines de récepteurs de cellules, de protéines structurales, directement dans les cellules d'un organisme. Il est possible d'introduire des ARN ribosomiques et de transport conjointement avec de l'ARN messager. Lorsque l'on introduit dans l'organisme du receveur de l'ARN codant une hormone particulière ou un antibiotique, des protéines de récepteurs de cellules ou des protéines structurales, ces substances sont synthétisées directement dans les cellules du receveur. L'utilisation d'ARN à la place de combinaisons de protéines constitue un avantage supplémentaire par rapport à d'autres analogues, en ce que l'ARN ne présente pas de propriétés immunogènes et ne provoque donc pas de réactions inflammatoires indésirables. On utilise l'ARN pour compléter un vaccin ou une autre substance destiné(e) à activer l'immunité du patient contre des antigènes existant dans ladite substance, tout ou partie de l'ARN participant à la synthèse de substances immunogènes contre lesquelles on souhaite activer l'immunité du patient ayant été préalablement enlevé desdites substances ou inactivé.
PCT/LT1998/000001 1997-02-28 1998-02-24 Utilisation de l'arn a la place d'une proteine, dans la production de substances bioactives ou pour la modulation de l'immunite specifique WO1998037900A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DE19882018T DE19882018T1 (de) 1997-02-28 1998-02-24 Verwendung der ausgewählten RNA anstelle eines Proteins bei der Produktion bioaktiver Substanzen oder für die spezifische Immunitätskontrolle
GB9918974A GB2337462A (en) 1997-02-28 1998-02-24 Use of the rna chosen instead of a protein in production of bioactive substances or for specific immunity control
JP53753298A JP2001517215A (ja) 1997-02-28 1998-02-24 生理活性物質の生産におけるタンパク質に代わる又は特定免疫制御用の選択されたｒｎａの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LT97-027A LT4475B (lt) 1997-02-28 1997-02-28 Informacinės ribonukleino rūgšties panaudojimas vaistinėse medžiagose, skirtose padidinti šios ribonukleino rūgšties koduojamo baltymo kiekį paciento ląstelėse
LT97-027 1997-02-28

Publications (1)

Publication Number Publication Date
WO1998037900A1 true WO1998037900A1 (fr) 1998-09-03

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PCT/LT1998/000001 WO1998037900A1 (fr) 1997-02-28 1998-02-24 Utilisation de l'arn a la place d'une proteine, dans la production de substances bioactives ou pour la modulation de l'immunite specifique

Country Status (5)

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JP (1) JP2001517215A (fr)
DE (1) DE19882018T1 (fr)
GB (1) GB2337462A (fr)
LT (1) LT4475B (fr)
WO (1) WO1998037900A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4213970A (en) * 1978-06-03 1980-07-22 Boehringer Ingelheim Gmbh Antiviral compositions containing a transfer-ribonucleic acid
WO1984000688A1 (fr) * 1979-12-21 1984-03-01 D Hinterland Lucien Dussourd Preparations immunostimulantes a base d'arn ribosomaux et procede de preparation des arn
FR2598619A1 (fr) * 1986-05-16 1987-11-20 Mafitra Management Services In Medicament antiviral a base d'acide nucleique modifie, et son procede de preparation
WO1993012814A2 (fr) * 1991-12-24 1993-07-08 The Immune Response Corporation Vaccination et procedes contre des maladies resultant de reponses pathogenes de populations de lymphocytes t specifiques
RU2016572C1 (ru) * 1987-03-23 1994-07-30 Хем Рисерч, Инк. Композиция для лечения спида
EP0676471A2 (fr) * 1994-03-08 1995-10-11 American Home Products Corporation Protéines effectrices pour rapamycine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2110946A1 (fr) 1992-12-09 1994-06-10 Elazar Rabbani Methode pour rendre un element du corps immunocompatible au moyen d'un construit d'acide nucleique, construit d'acide nucleique servant a inhiber ou a reguler la fonction d'un gene de la reponse immunitaire et element immunocompatible contenant un construit d'acide nucleique servant a inhiber ou a reguler la fonction d'un gene de la reponse

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4213970A (en) * 1978-06-03 1980-07-22 Boehringer Ingelheim Gmbh Antiviral compositions containing a transfer-ribonucleic acid
WO1984000688A1 (fr) * 1979-12-21 1984-03-01 D Hinterland Lucien Dussourd Preparations immunostimulantes a base d'arn ribosomaux et procede de preparation des arn
FR2598619A1 (fr) * 1986-05-16 1987-11-20 Mafitra Management Services In Medicament antiviral a base d'acide nucleique modifie, et son procede de preparation
RU2016572C1 (ru) * 1987-03-23 1994-07-30 Хем Рисерч, Инк. Композиция для лечения спида
WO1993012814A2 (fr) * 1991-12-24 1993-07-08 The Immune Response Corporation Vaccination et procedes contre des maladies resultant de reponses pathogenes de populations de lymphocytes t specifiques
EP0676471A2 (fr) * 1994-03-08 1995-10-11 American Home Products Corporation Protéines effectrices pour rapamycine

Also Published As

Publication number Publication date
LT97027A (en) 1998-09-25
GB2337462A (en) 1999-11-24
GB9918974D0 (en) 1999-10-13
DE19882018T1 (de) 2000-01-13
JP2001517215A (ja) 2001-10-02
LT4475B (lt) 1999-02-25

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