Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1999-03-22
2004-04-20
Falk, Anne-Marie (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C424S093600, C435S320100
Reexamination Certificate
active
06723315
ABSTRACT:
The present invention relates to a novel method for the treatment of motor neurone diseases and in particular of amyotrophic lateral sclerosis. It equally relates to vectors and pharmaceutical compositions allowing the prolonged expression of therapeutic factors, utilizable for the treatment of ALS. More precisely, the present invention relates to the treatment of ALS by systemic administration of therapeutic genes.
Amyotrophic lateral sclerosis (ALS), also known under the name of Charcot's disease and Lou Gehrig's disease was described for the first time by Charcot in 1865. ALS is a fatal disease resulting from the degeneration of motor neurones and corticospinal tracts. With an incidence at present of 2.5/100,000 and, constantly on the increase, a prevalence of 6-10/100,000, ALS affects 90,000 people in the developed countries, for the most part adults who are still young (between 50 and 60). The disease is accompanied by progressive paralysis, leading to the total loss of motor and respiratory functions and then to death with a delay of two to eight years after the appearance of the first symptoms (three years on average).
5% of the cases of ALS are of familial origin and 95% of the cases are sporadic. The physio-pathological origin of the sporadic forms of ALS remains unknown. Several hypotheses have been proposed. The motor neurons degeneration could result from an alteration in the metabolism of glutamate leading to an increase in the concentration of this exciter amino acid in the motor cortex and the spinal cord (“excitotoxic” hypothesis, review in Rothstein, 1995). The possibility of an autoinmune component has likewise been put forward on the basis of the presence of auto-antibody against the voltage-sensitive calcium channels in certain patients (review in Appel et al., 1995). The implication of environmental factors such as exposure to certain viruses (review in Gastaut, 1995), or to aluminium (Yase, 1984) is likewise possible.
The studies bearing on the hereditary forms of ALS have allowed it to be shown that point mutations in the gene for cupro-zinc containing superoxide dismutase, localized on the 21q22-1 chromosome, are responsible for the pathology in 20% of the familial forms (Rosen et al., 1993, review in Rowland, 1995). These mutations do not cause reduction of the dismutase activity of the SOD (review in Rowland, 1995). The mutated enzymes produce potentially cytotoxic hydroxyl radicals which are not produced by the wild-type SOD (Yim et al., 1996). The detailed study of the functional effect of the mutations on the enzymatic activity of the SOD and on the cellular viability in the end ought to allow the physiopathology of the familial forms of ALS to be understood, and, by extension, light to be thrown on the physiopathology of all of the forms of ALS.
Work bearing on factors capable of influencing the survival of the motor neurones has allowed a potential neuroprotector role of several neurotrophic factors to be demonstrated (review in Windebank, 1995; Henderson, 1995). Thus, motor neurone protection effects in vitro have been observed especially with BDNF (Oppenhoem et al., 1992, Yan et al., 1992 Sendtner et al., 1992, Henderson et al., 1993, Vejsada et al., 1995), NT-3 (Henderson et al., 1993), GDNF (Henderson et al., 1994, Oppenheim et al., 1995), three cytokines, CNTP, LIF (review in Henderson, 1995) and cardiotrophin-1 (Pennica at al., 1996), with IGF-1 (Lewis et al., 1993) and members of the FGF family (Hughes et al., 1993). All of these data suggest that the neurotrophic factors mentioned increase the survival of motor neurones under various experimental conditions. However, the use of neurotrophic factors in animal models of ALS or in human clinical trials as yet have not given convincing results. This use has never demonstrated any therapeutic effect and is always accompanied by undesirable secondary effects such as loss of weight, inflammation, fever, etc., which limit interest in trophic factors in the treatment of ALS and have led to the premature interruption of the first ALS-CNTF clinical trials by Regeneron (systemic administration) (Barinaga et al., 1994). It has thus not been possible as yet either to confirm interest in neurotrophic factors for the treatment of ALS, or to exploit their properties for a possible therapeutic approach.
On account of this, at the present time there is no means allowing ALS to be cured and very few medicaments having a therapeutic effect. Rilute® is the only treatment available today. The administration of riluzole (Rilutek®) allows the progression of the disease to be slowed, but no therapeutic effect has been demonstrated on the motor function. In addition, clinical trials based on the administration of CNTF have been interrupted prematurely for lack of results (Barinaga et al., 1994). Thus today there exists a real and important need to have available a method allowing motor neurone disorders to be treated, and in particular ALS.
The object of the present invention is especially to propose a novel approach for the treatment of the pathologies of motor neurones, such as ALS, based on gene therapy. More particularly, the present invention describes vector systems allowing the survival of motor neurones involved in these pathologies to be promoted directly, by the efficient and prolonged expression of certain trophic factors.
A first aspect of the invention relates to a method of treatment of ALS comprising the systemic administration of a nucleic acid coding for a neurotrophic factor. Another aspect of the invention relates to the use of a nucleic acid coding for a neurotrophic factor for the preparation of a pharmaceutical composition intended for the treatment of ALS. Another aspect of the invention resides in the construction of particular vectors allowing the expression of therapeutically effective quantities, in relation to ALS, of trophic factors. Another aspect of the invention relates to the administration of expression systems allowing the production of one or more trophic factors, as well as pharmaceutical compositions comprising the said expression systems. It likewise relates to the creation of novel vectors allowing the co-expression of trophic factors in vivo.
The present invention thus more precisely relates to a novel method of treatment of ALS based on the continuous in vivo expression of trophic factors.
The present invention now shows that it is possible in vivo to obtain a particularly pronounced therapeutic effect by in vivo production of nourotrophic factors. The applicant has especially shown that the in vivo injection of neurotrophic factor expression systems, by the systemic routs, allows a continuous production of therapeutic factors to be obtained, and that this production was sufficient to obtain a therapeutic benefit in the motor neurone pathologies, in particular ALS. Thus, the applicant has shown that the systemic administration of these expression systems leads to a very significant increase in the duration of life, accompanied by an improvement in the motor response evoked, as determined by electromyography. The results described demonstrate that this administration route allows an appropriate bioavailability of neurotrophic factors to be obtained, without toxicity effects. This therapeutic approach thus allows therapeutically active quantities of molecules to be produced, while remaining below the threshold of toxicity of these molecules. Thus, even though a protein of the size of a neurotrophic factor, administered in a systemic manner, only penetrates the nervous system with a low efficacy because of the blood-brain barrier, the method of the invention unexpectedly allows a significant therapeutic effect to be obtained. In addition, the method of the invention allows doses of therapeutic factors to be used which are below the toxicity threshold and do not induce secondary effects.
A first object of the invention thus resides in a method of treatment of ALS comprising the administration, by the systemic route, of an expression system of a neurotrophic factor. A
Haase Georg
Kahn Axel
Kennel Philippe
Mallet Jacques
Revah Frederic
Aventis Pharma S.A.
Falk Anne-Marie
Wiley Rein & Fielding LLP
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