Chemistry: molecular biology and microbiology – Vector – per se
Patent
1996-04-25
2000-10-31
Guzo, David
Chemistry: molecular biology and microbiology
Vector, per se
435 6, 435 913, 435 9131, 536 231, 536 241, 536 245, C07H 2104, C12N 1563
Patent
active
061401129
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to pharmaceutical compositions and to their use, in particular for the treatment of neurodegenerative diseases. It relates more especially to the use of compounds which act on the interaction between the sequence SEQ ID No. 1 and transcription factors for the preparation of a pharmaceutical composition intended for the treatment of neurodegenerative diseases.
The present invention is partly the outcome of the demonstration that the factor AP1 constitutes a mediator of neuronal degeneration, and that the use of compounds capable of inhibiting the activity of this complex can enable the process of neuronal death to be blocked. It is also the outcome of the demonstration that nucleic acids corresponding to the site of interaction of a transcription factor with DNA are capable of at least partially inhibiting the activity of this transcription factor.
To study the molecular mechanisms of neuronal degeneration, the Applicant used glutamate-induced toxicity as a model. Glutamate is the main excitatory neurotransmitter of the central nervous system. However, exposure to glutamate for abnormally long periods, or at concentrations higher than the physiological concentrations, may cause a neuronal toxicity designated by the term excitotoxicity (Olney Adv. Exp. Med. Biol. 203 (1986) 631). Many experimentally based lines of reasoning suggest that this type of toxicity contributes to the neuronal degeneration associated with ischaemia, hypoxia, hypoglycaemia and epileptic fits, or alternatively with cerebral trauma (Choi, J. Neurobiol. 23 (1992) 1261). Excitotoxicity is also considered to be involved in the pathogenesis of diseases such as Huntington's chorea (Young et al., Science 241 (1988) 981) and Alzheimer's disease (Koh et al., Brain Res. 533 (1990) 315; Mattson et al.; J. Neurosci. 12 (1992) 376).
More specifically, the Applicant studied the death induced by glutamate on embryonic rat cortical neurons in primary culture. Previous work had enabled it to be shown that the binding of glutamate to its membrane receptors caused depolarization of the cell membrane and an increase in intracellular calcium, which leads to the activation of a cascade of second messengers involving several families of enzymes. The Applicant studied at genetic level the modulation of the early response genes coding for transcription factors which, interacting in their turn with regulatory sequences of certain genes, will activate or repress their expression. More especially, the Applicant was able to show, surprisingly, that exposure of cortical cells to glutamate or to other excitotoxins such as NMDA causes an increase in the number of protein complexes capable of binding to the genomic sequence designated "12-O-tetradecanoylphorbol 13-acetate-responsive element", abbreviated to TRE [Schontal et al., Cell 54 (1988) 325; Lucibello et al., Oncogene 3 (1988) 43; Angel et al., Cell 49 (1987) 729; Bohman et al., Science 238 (1988) 1386]. This sequence of the TRE region is shown in SEQ ID No. 1. Furthermore, the Applicant also showed that, by sequestering the factors capable of binding to the sequence SEQ ID No. 1, cortical cells are saved from death induced by certain ranges of glutamate concentrations. This demonstrates that the sequence SEQ ID No. 1 plays the part of a mediator of neuronal degeneration, an observation which has never been reported in the prior art. The sequence SEQ ID No. 1 and the set of transcription factors capable of interacting with it hence constitutes a new pharmacological target in the treatment of neurodegenerative processes. Hence the invention lies in part in the use of compounds capable of blocking the activity of the sequence SEQ ID No. 1 for the treatment of neurodegenerative diseases.
Hence a first subject of the present invention lies in the use of a compound which at least partially inhibits the interaction between the sequence SEQ ID No. 1 and the transcription factors which interact with it, for the preparation of a pharmaceutical composition intended for the treatment and/or
REFERENCES:
Angel et al. "Phorbol Ester-Inducible Genes Contain a Common Cis Element Recognized by a TPA-Modulated Trans-Acting Factor" Cell, vol. 49: 729-739, Jun. 19, 1987.
Karin et al. "Metal-Responsive Elements Act as Positive Modulators of Human Metallothionine-IIA Enhancer Activity" Molecular and Cellular Biology vol. 7(2): 606-613, Feb. 1987.
Byrnes, A.P. et al "Adenovirus Gene Transfer Causes Inflamation in the Brain" Neuroscience, vol. 66, No. 4 pp. 1015-1024 1995.
Benson et al "General Selection for Specific DNA-Binding Activities". Genetics. vol. 114, No. 1 pp. 1-14 1986.
Stull et al "Antigene, Ribozyme and Aptamer Nucleic Acid Drugs: Progress & Prospects". Pharmaceutical Research vol. 12, No. 4 pp. 465-483 1995.
Lasil, D. "Liposomes within Liposomes", Nature vol. 387: 26-27, May 1, 1997.
Orkin et al "Report and Recomendations of the Pane to Assess the NiH Invesment in Research on Gene Therapy", Dec. 7, 1995.
Mallet Jacques
Revah Frederic
Robert Jean-Jacques
Guzo David
McGarry Sean
Rhone-Poulenc Rorer S.A.
LandOfFree
Pharmaceutical compositions and their use, namely for the treatm does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical compositions and their use, namely for the treatm, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical compositions and their use, namely for the treatm will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2050141