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AssigneesAventis Pharma S.A., Institut National De La Sante Et De La Recherche Medicale (Inserm)
InventorsFrançoise Finiels, Minerva Gimenez-Ribotta, Jacques Mallet, Alain Privat, Frédéric Revah
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The present invention relates to methods and compositions for delivering nucleic acids to motor neurons by administering the nucleic acids to muscle tissue. The invention relates to methods for treating pathologies of the nervous system, such as trauma and neurodegenerative diseases.
A method of muscle reinnervation and of inducing peripheral or collateral sprouting of motor axon endings in a mammal comprising administering directly to muscle tissue at least one nucleic acid encoding at least one neurotrophic factor chosen from NT-3 and CNTF, wherein said at least one nucleic acid is operably linked to a promoter, and wherein expression of said nucleic acid sequence in said mammal results in increased innervation of muscle tissue of the same medullary level as the muscle tissue that was administered the nucleic acid, increased peripheral sprouting of motor axon endings, increase collateral sprouting of motor endings, or combinations thereof.
A method of producing at least one neuroactive substance in mammalian motor neurons comprising administering directly to muscle tissue at least one nucleic acid encoding at least one neurotrophic factor chosen from NT-3 and CNTF, wherein said at least one nucleic acid is operably linked to a promoter, and wherein expression of said nucleic acid sequence in said mammal results in increased innervation of muscle tissue of the same medullary level as the muscle tissue that was administered the nucleic acid, increased peripheral sprouting of motor axon endings, increase collateral sprouting of motor axon ending, or combinations thereof.
A method of treating an impairment of the nervous system, comprising administering directly to muscle tissue at least one nucleic acid encoding at least one neurotrophic factor chosen from NT-3 and CNTF, wherein said at least one nucleic acid is operably linked to a promoter, and wherein expression of said nucleic acid sequence in said mammal results in increased innervation of muscle tissue of the same medullary level as the muscle tissue that was administered the nucleic acid, increased peripheral sprouting of motor axon endings, increase collateral sprouting of motor axon endings, or combinations thereof.
A composition useful for muscle reinnervation and for inducing the sprouting of motor axons endings comprising a first viral vector comprising a nucleic acid encoding CNTF operably linked to a promoter and a second viral vector comprising a nucleic acid encoding NT-3 operably linked to a promoter.
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For animal cells: viral vectors
Growth factors; Growth regulators: nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial…
Medicinal preparations containing genetic material which is inserted into cells of the
Drugs for dermatological disorders: for treating wounds, ulcers, burns, scars, keloids, or the like
Term ended 17 Jan 2017 (estimated)
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The present invention relates to methods of delivering a nucleic acid to motor neurons comprising administering the nucleic acid to muscle tissue. More particularly, the invention relates to methods for treating pathologies of the nervous system by intramuscular administration of a therapeutic gene, and gene transfer into medullary motor neurons. This invention also relates to compositions comprising the gene in a form suitable for intramuscular administration.
Neurodegenerative Disease
Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy of infancy (SMA), are often debilitating and resist curative treatment. For example, ALS is heavily disabling and invariably lethal. With an incidence of 2.5/100 000 in constant increase, a prevalence of 6-10/100,000 (Leigh, Pathogenic mechanisms in amyotrophic lateral sclerosis and other motor neurons disorders in Neurodegenerative diseases by CALNE, Saunders W. B. Eds, Philadelphia, U.S.A., 1994), ALS affects 90,000 patients in developed countries, mostly adults in their sixth decade. The disease is characterized by a progressive motor neuron degeneration leading to paralysis, to total loss of motor and respiratory functions, and eventually to death two to eight years after the appearance of the first clinical signs (mean duration after onset three years). ALS is of genetic origin in 5% of the patients, and sporadic in 95% of the cases. Point mutations in the gene encoding for Cu/Zn superoxide dismutase (SOD1) localised on chromosome 21q22-1 are responsible for the pathology in 20% of the familial cases (Rosen et al., Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature, 362, 59-62, 1993, review in Rowland, Amyotrophic lateral sclerosis: Human challenge for neuroscience, Proc. Natl. Acad. Sci. USA, 92, 1251-1253, 1995). The pathophysiological basis of the sporadic forms remains unknown. Although the use of Rilutek provides ALS patients with a modest increase in survival probability, there is no curative treatment available for this disorder.
FIG. 1: β-galactosidase labelling of longitudinal sections (50 μm) of rat spinal cord at the lumbar level, after intramuscular injection of adenovirus-β-galactosidase into the gastrocnemial muscle,
diffuse labelling of numerous motoneuronal cellular bodies (Δ),
more intense labelling of a few motor neurons at the level of the cellular body and of the neurites, revealing the typical morphology of the motor neurons ().
The present invention describes a particularly efficient method for the selective transfer of genes into motor neurons. The invention demonstrates that it is possible to specifically transfer a gene into the motor neurons by administration into the muscle. Applicants describe herein that adenoviruses are advantageously absorbed at the level of the neuromuscular junctions (motor endplates), and transported up to the cellular bodies of the motor neurons (ventral horn of the spinal cord) by retrograde transport along the motoneuronal axons. Intramuscular injections of recombinant adenoviruses expressing a trophic factor provides a particularly attractive mode of administration. After intramuscular injection adenoviruses will infect myotubes, thus allowing the trophic factor to be produced at the synaptic end of motoneurons and to be released continuously in the circulation. Intramuscular injections lead to retrograde transport of injected recombinant adenoviruses, allowing high yield infection of the afferent motoneurons (Finiels et al., Specific and efficient gene transfer strategy offers new potentialities for the treatment of motor neurone diseases. Neuroreport, 7, 373-378, 1995). This leads to the production of the transgene within the spinal cord.
Intramuscular administration of a therapeutic gene constitutes a new and very specific method for infecting the motor neurons by retrograde transport. The present invention enables one to target precisely the medullary stage on which it is desired to act, according to the location of the trauma and/or of the degeneration. In particular, the present invention advantageously enables one to specifically and unilaterally infect the motor neurons of the different medullary functional stages by following the precise map of the neuromuscular junctions. The present invention has been found to be less traumatic and more specific than stereotaxic injection into the medullary parenchyma, which is more diffuse and not restricted to the motor neurons.
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