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  Pharmaceutical Patents  

 

Title:  Isolated multiple sclerosis (MS)-associated retrovirus (MSRV) nucleic acids corresponding to the gag region
United States Patent: 
8,088,910
Issued: 
January 3, 2012

Inventors: 
Paranhos-Baccala; Glaucia (Lyons, FR), Komurian-Pradel; Florence (Poleymieux Au Mont D'Or, FR), Bedin; Frederic (Lyons, FR), Sodoyer; Mireille (Sainte Foy les Lyon, FR), Ott; Catherine (Lyons, FR), Mallet; Francois (Villeurbanne, FR), Perron; Herve (Lyons, FR), Mandrand; Bernard (Villeurbanne, FR)
Assignee: 
Biomerieux (Marcy l'Etoile, FR)
Appl. No.:  12/776,893
Filed: 
May 10, 2010


 

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Abstract

An isolated polynucleotide having a nucleotide sequence selected from the group consisting of (a) SEQ ID NO: 21, (b) the full-length sequences encoding a polypeptide having a peptide sequence selected from the group consisting of SEQ ID NOs: 25 and 26, and (c) the full-length complementary sequences to the sequences set forth in (a) or (b).

Description of the Invention

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is a demyelinizing disease of the central nervous system (CNS) of which the complete cause still remains unknown.

Numerous studies have supported the hypothesis for a viral etiology of the disease, but none of the known viruses tested has proved to be the causative agent tested for: a review of the viruses tested for in MS for many years has been carried out by E. Norrby and R. T. Johnson.

Recently, a retrovirus, different from the known human retroviruses, was isolated from patients suffering from MS. The authors were able to show that this retrovirus could be transmitted in vitro, that patients suffering from MS produced antibodies capable of recognizing proteins associated with the infection of the leptomeningeal cells by this retrovirus, and that the expression of the latter could be greatly stimulated by the immediate-early genes of some herpesviruses.

All these results argue in favor of the role in MS of at least one unknown retrovirus or of a virus having a reverse transcriptase (RT) activity which is detectable by the method published by H. Perron and termed "LM7-type RT" activity.

The studies by the applicant have made it possible to obtain two continuous cell lines infected with natural isolates obtained from two different patients suffering from MS, by a culture method as described in the document WO-A-93 20188, whose content is incorporated by reference into the present description. These two lines derived from cells of human choroid plexus, called LM7PC and PLI-2, were deposited at the E.C.A.C.C. on 22 Jul. 1992 and 8 Jan. 1993, respectively, under numbers 92 072201 and 93 010817, in accordance with the provisions of the Treaty of Budapest. Moreover, the viral isolates possessing an LM7-type RT activity have also been deposited at the E.C.A.C.C. under the overall name of "strains". The "strain" or isolate harbored by the PLI-2 line, called POL-2, was deposited at the E.C.A.C.C. on 22 Jul. 1992 under No. V92072202. The "strain" or isolate harbored by the LM7PC line, called MS7PG, was deposited at the E.C.A.C.C. on 8 Jan. 1993 under No. V93010816.

Using the above-mentioned cultures and isolates, characterized by biological and morphological criteria, efforts were then made to characterize the genetic material associated with the viral particles produced in these cultures.

The proportions of genome already characterized were used to develop molecular detection tests for the viral genome and immunoserological tests, using the amino acid sequences encoded by the nucleotide sequences of the viral genome, in order to detect the immune response directed against epitopes associated with the viral infection and/or expression.

These tools have already made it possible to confirm an association between MS and the expression of the sequences identified in the patents cited further on. However, the viral system discovered by the applicant is related to a complex retroviral system. Indeed, the sequences which are found to be encapsidated in the extracellular viral particles produced by the different cultures of cells of patients suffering from MS show clearly that there is co-encapsidation of retroviral genomes which are related but different from the "wild-type" retroviral genome which produces the infectious viral particles. This phenomenon was observed between replicative retroviruses and endogenous retroviruses belonging to the same family, or even heterologous retroviruses. The concept of endogenous retrovirus is very important in the context of our discovery because, in the case of MSRV-1, it has been observed that endogenous retroviral sequences comprising sequences homologous to the MSRV-1 genome exist in normal human DNA. The existence of endogenous retroviral elements (ERV) related to MSRV-1 through all or part of their genome explains the fact that the expression of the MSRV-1 retrovirus in human cells can interact with related endogenous sequences. These interactions are found in the case of pathogenic and/or infectious endogenous retroviruses (for example some ecotropic strains of the Murine Leukemia virus), in the case of exogenous retroviruses whose nucleotide sequence may be found partially or completely in the form of ERVs, in the genome of the host animal (e.g. mouse mammary tumor exogenous virus transmitted via milk). These interactions consist mainly of (i) a transactivation or co-activation of ERVs by the replicative retrovirus, (ii) an "illegitimate" encapsidation of related RNAs of ERVs, or of ERVs--or even of cellular RNAs--simply possessing compatible encapsidation sequences, into the retroviral particles produced by the expression of the replicative strain, which are sometimes transmissible and sometimes with an inherent pathogenicity, and (iii) relatively high recombinations between the co-encapsidated genomes, in particular in the reverse transcription phases, which lead to the formation of hybrid genomes, which are sometimes transmissible and sometimes with an inherent pathogenicity.

Thus, (i) various MSRV-1-related sequences have been found in purified viral particles; (ii) molecular analysis of the various regions of the MSRV-1 retroviral genome should be carried out by systematically analyzing the co-encapsidated, interfering and/or recombinant sequences which are generated by the infection and/or expression of MSRV-1; furthermore, some clones may have portions of defective sequences produced by the retroviral replication and the template and/or transcription errors caused by reverse transcriptase; (iii) the families of sequences related to the same retroviral genomic region are the supports for an overall diagnostic detection which may be optimized by the identification of invariable regions among the clones expressed and by the identification of reading frames responsible for the production of antigenic and/or pathogenic polypeptides which may only be produced by a portion, or even only one, of the clones expressed and under these conditions, the systematic analysis of the clones expressed in one region of a given gene makes it possible to evaluate the frequency of variation and/or recombination of the MSRV-1 genome in this region and to define the optimum sequences for the applications, in particular the diagnostic applications; (iv) the pathology caused by a retrovirus such as MRSV-1 may be a direct effect of its expression and of the proteins or peptides produced as a result, but also an effect of the activation, encapsidation, recombination of related or heterologous genomes and proteins or peptides produced as a result; thus, these genomes associated with the expression and/or infection by MSRV-1 are an integral part of the potential pathogenicity of this virus and therefore constitute diagnostic detection supports and particular therapeutic targets. Likewise, any agent which is associated with, or which is a cofactor for these interactions responsible for the pathogenicity in question, such as MSRV-2 or the gliotoxic factor described in the patent application published under the No. FR-2,716,198, can participate in the development of an overall and very effective strategy for therapeutic diagnosis, prognosis, monitoring and/or integrated therapy for MS in particular, but also for any other disease associated with the same agents.

In this context, a parallel discovery has been made in another autoimmune disease, rheumatoid arthritis (RA), which has been described in the French patent application published under the No. FR-2,731,356. This discovery shows that, by applying methodological approaches similar to those which were used in the studies by the applicant on MS, it has been possible to identify a retrovirus expressed in RA which shares the sequences described for MSRV-1 in MS and also the coexistence of an MSRV-2-associated sequence which is also described in MS. As regards MSRV-1, the sequences commonly detected in MS and RA relate to the pol and gag genes. On the basis of current knowledge, it is possible to combine the gag and pol sequences described with the MSRV-1 strains expressed in these two diseases.

The present patent application has as its object various results, supplementary in relation to those already protected by the French patent applications:

No. 92/04322 of 3 Apr. 1992, published under No. 2,689,519;

No. 92/13447 of 3 Nov. 1992, published under No. 2,689,521;

No. 92/13443 of 3 Nov. 1992, published under No. 2,689,520;

No. 94/01529 of 4 Feb. 1994, published under No. 2,715,936;

No. 94/01531 of 4 Feb. 1994, published under No. 2,715,939;

No. 94/01530 of 4 Feb. 1994, published under No. 2,715,938;

No. 94/01532 of 4 Feb. 1994, published under No. 2,715,937;

No. 94/14322 of 24 Nov. 1994, published under No. 2,727,428;

No. 94/15810 of 23 Dec. 1994, published under No. 2,728,585; and

Patent Application WO 97/06260.

SUMMARY OF THE INVENTION

The present invention relates, first of all, to a nucleic material, which may consist of a retroviral material, in isolated or purified state, which may be understood or characterized in various ways:

it comprises a nucleotide sequence chosen from the group which consists of (i) the sequences SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 30 and SEQ ID NO: 31; (ii) the sequences complementary to sequences (i); and (iii) the sequences equivalent to sequences (i) or (ii), in particular the sequences having, for every series of 100 contiguous monomers, at least 50%, and preferentially at least 70% homology with sequences (i) or (ii) respectively;

it encodes a polypeptide having, for every contiguous series of at least 30 amino acids, at least 50%, and preferably at least 70% homology with a peptide sequence chosen from the group which consists of SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 13, SEQ ID NO: 25 and SEQ ID NO: 26;

its pol gene comprises a nucleotide sequence identical or equivalent to a sequence chosen from the group which consists of SEQ ID NO: 4, SEQ ID NO: 16 and their complementary sequences;

the 5' end of its pol gene starts at nucleotide 1419 of SEQ ID NO: 21;

its pol gene encodes a polypeptide having, for every contiguous series of at least 30 amino acids, at least 50%, and preferably at least 70% homology with the peptide sequence SEQ ID NO: 5;

the 3' end of its gag gene ends at nucleotide 1418 of SEQ ID NO: 21;

its env gene comprises a nucleotide sequence identical or equivalent to a sequence chosen from the group which consists of SEQ ID NO: 9, and its complementary sequences;

its env gene comprises a nucleotide sequence which starts at nucleotide 1 of SEQ ID NO: 9 and ends at nucleotide 233 of SEQ ID NO: 6;

its env gene encodes a polypeptide having, for every contiguous series of at least 30 amino acids, at least 50%, and preferably at least 70% homology with the sequence SEQ ID NO: 10;

the U3R region of its 3' LTR comprises a nucleotide sequence which ends at nucleotide 617 of SEQ ID NO: 6;

the RU5 region of its 5' LTR comprises a nucleotide sequence which starts at nucleotide 755 of SEQ ID NO: 12 and ends at nucleotide 337 of SEQ ID NO: 30 or SEQ ID NO: 31;

a retroviral nucleic material comprising a sequence which starts at nucleotide 755 of SEQ ID NO: 12 and which ends at nucleotide 617 of SEQ ID NO: 6;

the retroviral nucleic material as defined above is in particular associated with at least one autoimmune disease such as multiple sclerosis or rheumatoid arthritis.

The invention also relates to a nucleotide fragment which corresponds to at least one of the following definitions:

it comprises or consists of a nucleotide sequence chosen from the group which consists of (i) the sequences SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 30 and SEQ ID NO: 31; (ii) the sequences complementary to sequences (i); and (iii) the sequences equivalent to sequences (i) or (ii), in particular the sequences having, for every series of 100 contiguous monomers, at least 50%, and preferentially at least 70% homology with sequences (i) or (ii) respectively;

it comprises or consists of a nucleotide sequence encoding a polypeptide having, for every contiguous series of at least 30 amino acids, at least 50%, and preferably at least 70% homology with a peptide sequence chosen from the group which consists of SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 13, SEQ ID NO: 25 and SEQ ID NO: 26.

Other subjects of the present invention are the following:

a nucleic probe for the detection of a retrovirus associated with multiple sclerosis and/or rheumatoid arthritis, capable of hybridizing specifically with any fragment defined above and belonging to the genome of said retrovirus; it advantageously possesses from 10 to 100 nucleotides, preferably from 10 to 30 nucleotides;

a primer for the amplification, by polymerization, of an RNA or of a DNA of a retrovirus associated with multiple sclerosis and/or rheumatoid arthritis, which comprises a nucleotide sequence identical or equivalent to at least a portion of the nucleotide sequence of a fragment defined above, in particular a nucleotide sequence having, for every series of 10 contiguous monomers, at least 50%, preferably at least 70% homology with at least said portion of said fragment; preferably the nucleotide sequence of a primer of the invention is chosen from SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 23, and SEQ ID NO: 24;

an RNA or a DNA and in particular a replication and/or expression vector, comprising a genomic fragment of the nucleic material or a fragment defined above;

a peptide encoded by any open reading frame belonging to a nucleotide fragment defined above, in particular a polypeptide, for example oligopeptide forming or comprising an antigenic determinant recognized by sera of patients infected with the MSRV-1 virus, and/or in whom the MSRV-1 virus has been reactivated; a preferential peptide comprises a sequence identical, partially or completely, or equivalent to a sequence chosen from SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 13, SEQ ID NO: 25 and SEQ ID NO: 26;

a diagnostic, prophylactic or therapeutic composition, in particular for inhibiting the expression of at least one retrovirus associated with multiple sclerosis and/or rheumatoid arthritis, comprising a nucleotide fragment defined above;

a method for detecting a retrovirus associated with multiple sclerosis and/or rheumatoid arthritis, in a biological sample, comprising the steps consisting of bringing an RNA and/or a DNA assumed to belong to or obtained from said retrovirus, or their complementary RNA and/or DNA, into contact with a composition comprising a nucleotide fragment defined above.

DEFINITIONS

Before detailing the invention, various terms used in the description and the claims are now defined.

Strain or isolate is understood to mean any infectious and/or pathogenic biological fraction containing, for example, viruses and/or bacteria and/or parasites, generating a pathogenic and/or antigenic power, harbored by a culture or a live host; by way of example, a viral strain according to the preceding definition may contain a co-infectious agent, for example a pathogenic protist.

The term "MSRV" used in the present description designates any pathogenic and/or infectious agent, as associated with MS, in particular a viral species, the attenuated strains of said viral species, or the interfering defective particles or particles containing co-encapsidated genomes or alternatively genomes recombined with a portion of the MSRV-1 genome, which are derived from this species. It is known that viruses and particularly viruses containing RNA exhibit variability, following in particular relatively high rates of spontaneous mutation, which will be taken into account below to define the concept of equivalence.

Human virus is understood to mean a virus capable of infecting or of being harbored by human beings.

Given all the natural or induced variations and/or recombination which may be encountered in practice in the present invention, the objects thereof, defined above and in the claims, have been expressed by comprising the equivalents or derivatives of the various biological materials defined below, in particular homologous nucleotide or peptide sequences.

The variant of a virus or of a pathogenic and/or infectious agent according to the invention comprises at least one antigen recognized by at least one antibody directed against at least one corresponding antigen of said virus and/or of said pathogenic and/or infectious agent, and/or a genome in which any portion is detected by at least one hybridization probe, and/or at least one nucleotide amplification primer specific for said virus and/or pathogenic and/or infectious agent, under defined hybridization conditions well known to persons skilled in the art.

According to the invention, a nucleotide fragment or an oligonucleotide or a polynucleotide is a stretch of monomers, or a biopolymer, characterized by the informational sequence of the natural nucleic acids, which is capable of hybridizing to any other nucleotide fragment under predefined conditions, it being possible for the stretch to contain monomers of different chemical structures and to be obtained from a natural nucleic acid molecule and/or by genetic recombination and/or by chemical synthesis; a nucleotide fragment may be identical to a genomic fragment of the MSRV-1 virus considered by the present invention, in particular a gene of the latter, for example pol or env in the case of said virus.

Thus, a monomer may be a natural nucleic acid nucleotide in which the constituent components are a sugar, a phosphate group and a nitrogen base; in RNA, the sugar is ribose; in DNA, the sugar is 2-deoxyribose; depending on whether DNA or RNA is involved, the nitrogen base is chosen from adenine, guanine, uracil, cytosine, thymine; or the nucleotide may be modified in at least one of the three constituent components; by way of example, the modification may occur at the level of the bases, generating modified bases such as inosine, 5-methyl-deoxycytidine, deoxyuridine, 5-dimethylaminodeoxyuridine, 2,6-diaminopurine, 5-bromodeoxyuridine and any other modified base promoting hybridization; at the level of the sugar, the modification may consist in the replacement of at least one deoxyribose with a polyimide, and at the level of the phosphate group, the modification may consist in its replacement with esters, in particular chosen from the esters of diphosphate, of alkyl and arylphosphonate and of phosphorothioate.

"Informational sequence" is understood to mean any ordered series of monomers, whose chemical nature and in which the order in a reference direction, constitute or otherwise a functional information of the same quality as that for the natural nucleic acids.

Hybridization is understood to mean the process during which, under appropriate operating conditions, two nucleotide fragments, having sufficiently complementary sequences, become annealed to form a complex, in particular a double or triple, structure, preferably in helical form.

A probe comprises a nucleotide fragment synthesized by the chemical route or obtained by digestion or enzymatic cleavage of a longer nucleotide fragment, comprising at least six monomers, advantageously from 10 to 100 monomers, preferably 10 to 30 monomers, and possessing a hybridization specificity under defined conditions; preferably, a probe possessing less than 10 monomers is not used alone, but is used in the presence of other probes which are equally short in length or otherwise; under certain specific conditions, it may be useful to use probes which are greater than 100 monomers in size; a probe may be used in particular for diagnostic purposes, and it may be, for example, capture and/or detection probes.

The capture probe may be immobilized on a solid support by any appropriate means, that is to say directly or indirectly, for example by covalent bonding or passive adsorption.

The detection probe may be labeled by means of a marker chosen in particular from radioactive isotopes, enzymes chosen in particular from peroxidase and alkaline phosphatase and those capable of hydrolyzing a chromogenic, fluorigenic or luminescent substrate, chromophoric chemical compounds, chromogenic, fluorigenic or luminescent compounds, analogs of nucleotide bases, and biotin.

The probes used for diagnostic purposes of the invention may be used in all known hybridization techniques, and in particular the so-called "DOT-BLOT" technique, "SOUTHERN BLOT" technique, "NORTHERN BLOT" technique which is a technique identical to the "SOUTHERN BLOT" technique but which uses RNA as target, the SANDWICH technique; advantageously, the SANDWICH technique is used in the present invention, comprising a specific capture probe and/or a specific detection probe, it being understood that the capture probe and the detection probe must have a nucleotide sequence which is at least partially different.

Any probe according to the present invention may hybridize in vivo or in vitro with the RNA and/or with the DNA, in order to block the replication, in particular translation and/or transcription, phenomena and/or to degrade said DNA and/or RNA.

A primer is a probe comprising at least six monomers, and advantageously from 10 to 30 monomers, possessing hybridization specificity under defined conditions, for the initiation of an enzymatic polymerization, for example in an amplification technique such as PCR (Polymerase Chain Reaction), in an extension method such as sequencing, in a reverse transcription method and the like.

Two nucleotide or peptide sequences are said to be equivalent or derived with respect to each other, or with respect to a reference sequence, if functionally the corresponding biopolymers can play substantially the same role, without being identical, in relation to the application or use considered, or in the technique in which they are involved; particularly equivalent are two sequences obtained because of the natural variability, in particular spontaneous mutation, of the species from which they were identified, or induced mutation, as well as two homologous sequences, the homology being defined below.

"Variability" is understood to mean any spontaneous or induced modification of a sequence, in particular by substitution, and/or insertion, and/or deletion of nucleotides and/or of nucleotide fragments, and/or extension and/or shortening of the sequence at least at one of the ends; a nonnatural variability may result from the genetic engineering techniques used, for example from the choice of the degenerate or nondegenerate synthetic primers selected to amplify a nucleic acid; this variability may result in modifications of any starting sequence, considered as a reference, and which may be expressed by a degree of homology with respect to said reference sequence.

Homology characterizes the degree of identity of two compared nucleotide or peptide fragments; it is measured by the percentage identity which is in particular determined by direct comparison of nucleotide or peptide sequences, with respect to reference nucleotide or peptide sequences.

Any nucleotide fragment is said to be equivalent to or derived from a reference fragment if it has a nucleotide sequence equivalent to the sequence of the reference fragment; according to the preceding definition, in particular equivalent to a reference nucleotide fragment are:

(a) any fragment capable of hybridizing, at least partially, with the complementary to the reference fragment,

(b) any fragment whose alignment with the reference fragment leads to the identification of identical contiguous bases, in a greater number than with any other fragment obtained from another taxonomic group,

(c) any fragment resulting or capable of resulting from the natural variability of the species from which it is obtained,

(d) any fragment which may result from genetic engineering techniques applied to the reference fragment,

(e) any fragment, containing at least eight contiguous nucleotides, encoding a peptide homologous or identical to the peptide encoded by the reference fragment,

(f) any fragment different from the reference fragment through insertion, deletion, substitution of at least one monomer, extension, or shortening at least at one of its ends; for example, any fragment corresponding to the reference fragment, flanked at least at one of its ends by a nucleotide sequence not encoding a polypeptide.

Polypeptide is understood to mean in particular any peptide of at least two amino acids, in particular oligopeptide, protein, extracted, separated, or substantially isolated or synthesized, through the involvement of humans, in particular those obtained by chemical synthesis, or through expression in a recombinant organism.

Polypeptide partially encoded by a nucleotide fragment is understood to mean a polypeptide having at least three amino acids encoded by at least nine contiguous monomers included in said nucleotide fragment.

An amino acid is said to be analogous to another amino acid when their respective physicochemical characteristics, such as polarity, hydrophobicity and/or basicity, and/or acidity, and/or neutrality, are substantially the same; thus, a leucine is analogous to an isoleucine.

Any polypeptide is said to be equivalent to or derived from a reference polypeptide if the polypeptides compared have substantially the same properties, and in particular the same antigenic, immunological, enzymatic and/or molecular recognition properties; in particular equivalent to a reference polypeptide is:

(a) any polypeptide possessing a sequence in which at least one amino acid has been replaced by an analogous amino acid,

(b) any polypeptide having an equivalent peptide sequence, obtained by natural or induced variation of said reference polypeptide, and/or of the nucleotide fragment encoding said polypeptide,

(c) a mimotope of said reference polypeptide,

(d) any polypeptide from whose sequence one or more amino acids of the L series are replaced by an amino acid of the D series, and vice versa,

(e) any polypeptide into whose sequence a modification of the side chains of the amino acids has been introduced, such as for example an acetylation of the amine-containing functions, a carboxylation of the thiol functions, an esterification of the carboxyl functions,

(f) any polypeptide in whose sequence one or more peptide bonds have been modified, such as for example the carba, retro, inverso, retro-inverso, reduced, and methylene-oxy bonds,

(g) any polypeptide in which at least one antigen is recognized by an antibody directed against a reference polypeptide.

The percentage identity characterizing the homology between two peptide fragments compared is according to the present invention at least 50% and preferably at least 70%.

Given that a virus possessing a reverse transcriptase enzymatic activity may be genetically characterized both in RNA and DNA form, both the viral DNA and RNA will be mentioned in order to characterize the sequences relative to a virus possessing such a reverse transcriptase activity, termed MSRV-1 according to the present description.

The expressions of order which are used in the present description and the claims, such as "first nucleotide sequence", are not selected to express a particular order, but to define the invention more clearly.
 

Claim 1 of 13 Claims

1. An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of: (a) SEQ ID NO: 21, (b) the full-length sequences encoding a polypeptide having a peptide sequence selected from the group consisting of SEQ ID NOs: 25 and 26, and (c) the full-length complementary sequences to the sequences set forth in (a) or (b).
 

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