Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1997-11-26
2003-06-24
Salimi, Ali R. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S187100, C424S185100, C435S005000, C435S006120, C435S069100, C530S350000, C536S023720, C536S024300, C536S024320
Reexamination Certificate
active
06582703
ABSTRACT:
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), the cause of which remains as yet unknown.
“Multiple sclerosis (MS) is the most common neurological disease of young adults with a prevalence in Europe and North America of between 20 and 200 per 100,000. It is characterized clinically by a relapsing/remitting or chronic progressive course, frequently leading to severe disability. Current knowledge suggests that MS is associated with autoimmunity, that genetic background has an important influence and that “infectious” agent(s) may be involved. Indeed, many viruses have been proposed as possible candidates but as yet, none of them has been shown to play an aetiological role.
Many studies have supported the hypothesis of a viral aetiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2).
The discovery of pathogenic retroviruses in man (HTLVs and HIVs) was followed by great interest in their ability to impair the immune system and to provoke central nervous system inflammation and/or degeneration. In the case of HTLV-1, its association with a chronic inflammatory demyelinating disease in man (48) led to extensive investigations to search for an HTLV1-like retrovirus in MS patients. However, despite initial claims, the presence of HTLV-1 or HTLV-like retroviruses was not confirmed.
Recently, a retrovirus different from the known human retroviruses has been isolated in patients suffering from MS (3, 4, and 5).
In 1989, the authors described the production of extracellular virions, associated with reverse transcriptase (RT) activity, by a culture of leptomeningeal cells (LM7) obtained from the cerebrospinal fluid of a patient with MS (3). This was followed by similar findings in monocyte cultures from a series of MS patients (5). Neither viral particles nor viral RT-activity were found in control individuals. Furthermore, the authors were able to transfer the LM7 virus to non-infected leptomeningeal cells in vitro (26). The molecular characterization of the “LM7” retrovirus was a prerequisite for further evaluation of its possible role in MS. Considerable difficulties arose from the absence of continuously productive retroviral cultures and from the low levels of expression in the few transient cultures. The strategy described here focused on RNA from extracellular virions, in order to avoid non-specific detection of cellular RNA and of endogenous elements from contaminating human DNA. A specific retroviral sequence associated with virions produced by cell cultures from several MS patients has been identified. The entire sequence of this novel retroviral genome is currently being obtained using RT-PCR on RNA from extracellular virions. The retrovirus previously called “LM7 virus” corresponds to an oncovirus and is now designated MSRV (Multiple Sclerosis-associated RetroVirus).
The authors were also 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 leptomeningeal cells by this retrovirus, and that the expression of the latter could be strongly stimulated by the immediate-early genes of some herpesviruses (6).
All these results point to the role in MS of at least one unknown retrovirus or of a virus having reverse transcriptase activity which is detectable according to the method published by H. Perron (3) and qualified as “LM7-like RT” activity. The content of the publication identified by (3) is incorporated in the present description by reference.
Recently, the Applicant's studies have enabled two continuous cell lines infected with natural isolates originating from two different patients suffering from MS to be obtained by a culture method as described in the document WO-A-93/20188, the content of which is incorporated in the present description by reference. These two lines, derived from human choroid plexus cells, designated LM7PC and PLI-2, were deposited with the ECACC on Jul. 22, 1992 and Jan. 8, 1993, respectively, under numbers 92072201 and 93010817, in accordance with the provisions of the Budapest Treaty. Moreover, the viral isolates possessing LM7-like RT activity were also deposited with the ECACC under the overall designation of “strains”. The “strain” or isolate harboured by the PLI-2 line, designated POL-2, was deposited with the ECACC on Jul. 22, 1992 under No. V92072202. The “strain” or isolate harboured by the LM7PC line, designated MS7PG, was deposited with the ECACC on Jan. 8, 1993 under No. V93010816.
Starting from the cultures and isolates mentioned above, characterized by biological and morphological criteria, the next step was to endeavour to characterize the nucleic acid material associated with the viral particles produced in these cultures.
The portions of the genome which have already been characterized have been used to develop tests for molecular detection of the viral genome and iunmunoserological 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 infection and/or viral expression.
These tools have already enabled an association to be confirmed between MS and the expression of the sequences identified in the patents cited later. However, the viral system discovered by the Applicant is related to a complex retroviral system. In effect, the sequences to be found encapsidated in the extracellular viral particles produced by the different cultures of cells of patients suffering from MS show clearly that there is coencapsidation of retroviral genomes which are related but different from the “wild-type” retroviral genome which produces the infective viral particles. This phenomenon has been observed between replicative retroviruses and endogenous retroviruses belonging to the same family, or even heterologous retroviruses. The notion of endogenous retroviruses is very important in the context of our discovery since, 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 by all or part of their genome explains the fact that the expression of the MSRV-1 retrovirus in human cells is able to interact with closely related endogenous sequences. These interactions are to be found in the case of pathogenic and/or infectious endogenous retroviruses (for example some ecotropic strains of the murine leukaemia virus), and in the case of exogenous retroviruses whose nucleotide sequence may be found partially or wholly, in the form of ERVs, in the host animal's genome (e.g. mouse exogenous mammary tumor virus transmitted via the milk). These interactions consist mainly of (i) a trans-activation or coactivation of ERVs by the replicative retrovirus (ii) and “illegitimate” encapsidation of RNAs related to ERVS, or of ERVs—or even of cellular RNAs—simply possessing compatible encapsidation sequences, in the retroviral particles produced by the expression of the replicative strain, which are sometimes transmissible and sometimes with a pathogenicity of their own, and (iii) more or less substantial recombinations between the coencapsidated genomes, in particular in the phases of reverse transcription, which lead to the formation of hybrid genomes, which are sometimes transmissible and sometimes with a pathogenicity of their own.
Thus, (i) different sequences related to MSRV-1 have been found in the purified viral particles; (ii) molecular analysis of the different regions of the MSRV-1 retroviral genome should be carried out by systematically analyzing the coencapsidated, interfering and/or recombined sequences which are generated by the infection and/or expression of MSRV-1; furthermore, some clones may have defective sequence portions produ
Bedin Frederic
Beseme Frederic
Jolivet-Reynaud Colette
Komurian-Pradel Florence
Mandrand Bernard
Bio Merieux
Oliff & Berridg,e PLC
Salimi Ali R.
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