Centre National De La Recherche Scientifique

Polyplus Transfection

Rhone-poulenc Rorer S.a.

Universitéde Strasbourg

Polyplus-transfection Sa

Aventis Pharma S.a.

Centre National De La Recherche Scientifique-cnrs

Jean-Paul Behr

Jean-Serge Remy

Daniel Scherman

Barbara Demeneix

Patrick Erbacher

Jean-Philippe Loeffler

Anne-Laure Bolcato Bellemin

Mitsuharu Kotera

Bertrand Schwartz

Emilie Voirin

Otmane Boussif

Bénédicte Pons

Benedicte Pons

Patrick Neuberg

Mojgan Mergny

Franck Lezoualch

Nadège Pfender

The invention relates to oligonucleotide-oligocation molecules ABH that can be synthetized via automated phosphoramidite chemistry having oligonucleotides moieties Ai and oligocations moieties Bj, wherein .Ais an i-mer oligonucleotide residue, with i=5 to 50, where nucleotide A is an oligomer with naturally or non naturally occurring nucleobases and/or pentafuranosyl groups and/or native phosphodiester bonds, for example selected from the group comprising deoxyribo, ribo, locked (LNA) nucleotides as well as their chemical modifications or substitutions such as phosphorothioate, 2'-fluoro, 2&#x2032;-O-alkyl, or a marker group such as a fluorescent agent, .Bj is a j-mer organic oligocation moiety, with j=1 to 50, where B is selected from the group comprising .&#x2014;HPO&#x2014;R&#x2014;(X&#x2014;R)&#x2014;X&#x2014;R&#x2014;O&#x2014;, where R, Rn and R, identical or different, are lower alkylene, X is NH or NC(NH), n varies from 1 to 5 and n1=2 to 20, .&#x2014;HPO&#x2014;R&#x2014;CH(RX)&#x2014;R&#x2014;O&#x2014;, where Ris lower alkylene, Rand R, identical or different, are lower alkylene and Xis putrescine, spermidine or spermine residue, .&#x2014;HPO&#x2014;R-(aa)-R&#x2014;O&#x2014;, where Ris lower alkylene and Ris lower alkylene, serine, a natural aminoalcohol, (aa)is a peptide containing natural aminoacids with cationic side chains, such as Arginine, Lysine, Ornithine, -Histidine, Diaminopropionic acid and n2=2 to 20.

Cationic oligonucleotides, automated methods for preparing same and their uses

The invention relates to compositions comprising double-stranded oligonucleotides of identical or different sequences and/or length, said oligonucleotides having sequencesNN. . . NN. . . Nwherein&#x2014;N. . . Nis half of a double-stranded 19-28 mer oligonucleotide of sequence complementary to a target nucleic acid sequence present in a living cell, and&#x2014;N. . . Nis a 3-50 mer overhang of sequence allowing oligomerization of said double-stranded oligonucleotide. Compositions of transfection comprising said oligonucleotide compositions and there used for therapeutical application.

Oligonucleotides for RNA interference and biological applications thereof

The invention relates to oligonucleotide-oligocation molecules ABH that can be synthetized via automated phosphoramidite chemistry having oligonucleotides moieties Ai and oligocations moieties Bj, wherein &#x2022;Ais an i-mer oligonucleotide residue, with i=5 to 50, where nucleotide A is an oligomer with naturally or non naturally occurring nucleobases and/or pentafuranosyl groups and/or native phosphodiester bonds, for example selected from the group comprising deoxyribo, ribo, locked (LNA) nucleotides as well as their chemical modifications or substitutions such as phosphorothioate, 2'-fluoro, 2&#x2032;-O-alkyl, or a marker group such as a fluorescent agent, &#x2022;Bj is a j-mer organic oligocation moiety, with j=1 to 50, where B is selected from the group comprising &#x2022;&#x2014;HPO&#x2014;R&#x2014;(X&#x2014;R)&#x2014;X&#x2014;R&#x2014;O&#x2014;, where R, Rn and R, identical or different, are lower alkylene, X is NH or NC(NH), n varies from 1 to 5 and n1=2 to 20, &#x2022;&#x2014;HPO&#x2014;R&#x2014;CH(RX)&#x2014;R&#x2014;O&#x2014;, where Ris lower alkylene, Rand R, identical or different, are lower alkylene and Xis putrescine, spermidine or spermine residue, &#x2022;&#x2014;HPO&#x2014;R-(aa)-R&#x2014;O&#x2014;, where Ris lower alkylene and Ris lower alkylene, serine, a natural aminoalcohol, (aa)is a peptide containing natural aminoacids with cationic side chains, such as Arginine, Lysine, Ornithine, -Histidine, Diaminopropionic acid and n2=2 to 20.

The invention relates to compositions comprising double-stranded oligonucleotides of identical or different sequences and/or length, said oligonucleotides having sequencesNN. . . NN. . . Nwherein&#x2014;N. . . Nis half of a double-stranded 19-28mer oligonucleotide of sequence complementary to a target nucleic acid sequence present in a living cell, and&#x2014;N. . . Nis a 3-50mer overhang of sequence allowing oligomerization of said double-stranded oligonucleotide. Compositions of transfection comprising said oligonucleotide compositions and there used for therapeutical application.

The invention relates to compositions of transfection comprising an oligonucleotide and an amphiphilic cationic molecule of formula (I) wherein, &#x2014;X is N&#x2014;R, S or O, Rbeing a C1-C4 alkyl radical or an hydroxylated C3-C6 alkyl radical, Rand R, identical or different, represent H or a C1-C4 alkyl radical, or Rand Rare linked together to form a saturated or unsaturated cycle or a heterocycle having 5 or 6 elements, E is a C1-C5 alkyl spacer, Rand R, identical or different, represent saturated or unsaturated, linear or branched, C10-C36 hydrocarbon or fluorocarbon chains, optionally comprising C3-C6 cycloalkyl, A&#x2212; is a biocompatible anion. The invention relates to compositions active for oligonucleotides delivery into eukaryotic cells in culture, ex vivo or in vivo. The invention relates to compositions of transfection comprising an oligonucleotide active for RNA interference. Such compositions can be used as tools for biological studies or as drugs for therapies.

Compositions for transfection of oligonucleotides active for gene silencing and their biological and therapeutical applications

The present invention relates to compositions comprising at least one nucleic acid and one lipopolyamine, and their utilisation in gene therapy, particularly for the transfert in vivo of nucleic acids.

Composition containing nucleic acids, preparation and uses

Nucleic acid containing composition, preparation and uses of same

New lipopolyamines of general formula (I), their salts, their preparation and their use. ##STR1## n=1 to 5 and m=2 to 6 R represents a radical ##STR2## (R.sub.1 and R.sub.2 : aliphatic radical containing 12 to 22 carbon atoms; R: hydrogen atom or alkyl radical optionally substituted with phenyl), or a radical ##STR3## (X=CH.sub.2, CO; R.sub.3 and R.sub.4 aliphatic radical containing 11 to 21 carbon atoms), their preparation and their use. The lipopolyamines of general formula (I) are especially useful as vectors for the transfection of eukaryotic cells.

Lipopolyamines, their preparation and their use

Intermediate compounds useful for producing transfecting lipopolyamines, comprising: ##STR1## wherein m is an integer between 2 and 6 inclusive, wherein n is an integer between 2 and 5 inclusive, wherein R.sub.5 represents a hydrogen atom or a carboxyl radical but no more than one R.sub.5 represents a carboxyl, the values of m in the different fragments (CH).sub.m may be identical or different, and wherein the symbol Z R.sub.5 represent a group protecting the amine function.

New lipopolyamines, their preparation and their use

New lipopolyamines of general formula (I), their salts, their preparation and their use. ##STR1## n=1 to 5 and m=2 to 6; R represents a radical ##STR2## (R.sub.1 and R.sub.2 : aliphatic radical containing 12 to 22 carbon atoms; R: hydrogen atom or alkyl radical optionally substituted with phenyl), or a radical ##STR3## (X=CH.sub.2, CO; R.sub.3 and R.sub.4 aliphatic radical containing 11 to 21 carbon atoms), their preparation and their use. The lipopolyamines of general formula (I) are especially useful as vectors for the transfection of eukaryotic cells.

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Strasbourg, France

Jean-Paul Behr