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WO1996033731A1 - Procedes d'utilisation des facteurs neurotrophiques pour faciliter les greffes de neurones - Google Patents

Procedes d'utilisation des facteurs neurotrophiques pour faciliter les greffes de neurones Download PDF

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Publication number
WO1996033731A1
WO1996033731A1 PCT/US1996/005814 US9605814W WO9633731A1 WO 1996033731 A1 WO1996033731 A1 WO 1996033731A1 US 9605814 W US9605814 W US 9605814W WO 9633731 A1 WO9633731 A1 WO 9633731A1
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Prior art keywords
neurons
bdnf
mammal
neurotrophic factor
grafted
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PCT/US1996/005814
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English (en)
Inventor
David M. Yurek
Stanley J. Wiegand
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Regeneron Pharmaceuticals, Inc.
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Priority to AU55767/96A priority Critical patent/AU5576796A/en
Publication of WO1996033731A1 publication Critical patent/WO1996033731A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3

Definitions

  • the present invention relates to methods of using neurotrophic factors to enhance neuronal grafts. More specifically, the present invention relates to a method of promoting the structural and functional integration of neurons grafted into the central nervous system of a mammal by administering a neurotrophic factor to the central nervous system of the mammal.
  • various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application.
  • Neuronal grafting has emerged recently as a potential approach to central nervous system (CNS) therapy.
  • CNS central nervous system
  • the replacement or addition of cells to the CNS which are able to produce and secrete therapeutically useful substances may offer the advantage of averting repeated drug administration or provide a method of treatment for conditions for which drug therapy is currently nonexistent or suboptimal.
  • Neuronal grafting also offers the potential for replacement of lost neuronal circuits which cannot be accomplished by drug therapy alone. While the concepts and basic procedures of neuronal grafting have long been known, most of the factors that may optimize the survival of grafted cells have only recently been discovered and are still only partially vmderstood. (Bjorklund et al., in Neural Grafting in the Mammalian CNS, p.
  • Neuronal grafting has reached a level of experimental clinical application in Parkinson's disease.
  • Parkinson's disease is a disorder characterized by a loss of dopaminergic neurons in the substantia-nigra of the midbrain.
  • the symptoms of the disease include
  • SUBSTITUTE SHEET (RULE 25) tremor, rigidity and bradykinesia. It has been suggested that neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS), may occur due to the loss or decreased availability of a substance, a neurotrophic factor, specific for a particular population of neurons affected in each disorder. (Phillips, H.S., et al., Neuron 7: 695-702 (1991)).
  • neurotrophic factor refers to a substance or combination of substances whose primary function is to increase and /or maintain the survival of a neuronal population, but may also affect the outgrowth of neuron processes and /or the metabolic activity of a neuron.
  • neurotrophic factors affecting specific neuronal populations in the central nervous system have been reported. It may be that the loss of such specific neurotrophic factors is responsible for age-related declines in cell survival and /or function. While the cellular source remains unclear, there is evidence to suggest that neurons and glia are both capable of secreting neurotrophic factors. (Lindsay,
  • Parkinson's disease is progressive, but symptoms of this disease can be ameliorated by replacement of dopamine through the administration of pharmacological doses of the precursor for dopamine, L-DOPA.
  • Trophic factor expression is dynamic during the course of nervous system development, with specific factors being differentially expressed in various regions of the nervous system, often with distinct temporal periodicities.
  • transplanted fetal neurons may be limited, at least in part, by deficiencies in the trophic environment provided by the mature or damaged brain.
  • trophic factors include fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, transforming growth factor-a, and glial cell derived neurotrophic factor as well as several Nerve Growth Factor (NGF) related neurotrophins.
  • NGF Nerve Growth Factor
  • BDNF Brain-Derived Neurotrophic Factor
  • NT-3 Neurotrophin-3
  • NT-4/5 Neurotrophin-4/5
  • BDNF is a member of the neurotrophin family of neuronal survival and differentiation factors which also includes NGF, NT-3 and NT-4/5.
  • BDNF has been shown to enhance the dopamine (DA) uptake of fetal nigral DA neurons in cell culture (Beck, K.D., et al, Neuroscience 52: 855-866 (1993); Knusel, B., et al., PNAS (USA) 88:961-965 (1991)) and to partially protect DA neurons from the toxic effects of the neurotoxins N-methyl-4-phenylpyridinium ion and 6- hydroxydopamine (6-OHDA) (Hyman, C, et al. Nature 350:230-232 (1991); Spina, M.B.
  • DA dopamine
  • BDNF has also been shown to have a strong supportive effect on the survival of cultured nigral DA neurons.
  • BDNF has also been shown to have a strong supportive effect on the survival of cultured nigral DA neurons.
  • Hyman, C, et al. Nature 350:230-232 (1991); Knusel, B., et al., PNAS (USA) 88:961-965 (1991) These findings suggested that BDNF might have a survival-promoting effect on grafted DA neurons in vivo.
  • Applicants thus decided to determine whether the expression of neurotrophic factors in the neostriatum might be developmentally regulated and further investigated the treatment of grafts of DA neurons with neurotrophic factors in an effort to promote the structural and functional integration of the neurons into the graft recipient.
  • the present invention relates to a method of promoting the structural and functional integration of neurons grafted into the central nervous system of a mammal comprising administering a neurotrophic factor to the central nervous system of the mammal, thereby promoting the structural and functional integration of the grafted neurons.
  • a neurotrophic factor is administered to the central nervous system during a time period in the ontogenic development of the grafted neurons when the neurons are optimally responsive to the neurotrophic factor.
  • the neurotrophic factor is selected from the group consisting of NGF, BDNF, NT-3, NT-4/5, and derivatives thereof. In another embodiment, the neurotrophic factor is selected from the group consisting of CNTF, GDNF, and derivatives thereof. In a further embodiment of the invention, at least two neurotrophic factors are administered and are selected from the group consisting of CNTF, GDNF, NGF, BDNF, NT-3, NT-4/5, and derivatives thereof.
  • the grafted neurons are dopaminergic neurons.
  • the dopaminergic neurons may be derived from a mammal of the same species as the graft recipient or from a mammal of a different species as the graft recipient.
  • the dopaminergic neurons are contained in fetal ventral mesencephalic tissue.
  • the recipient mammal is a human and the graft is made to the striatum of the brain as a treatment for Parkinson's disease.
  • Figure 1 Amphetamine-induced rotational behavior before and after transplant /infusion treatment. Rotational behavior was assessed 3 weeks after the animals received a unilateral 6-OHDA lesion [PREGRAFT] and 3, 4, and 5 weeks after surgical implantation of either transplants /pumps or pumps alone. BDNF [0.75 ⁇ g/ ⁇ l] was delivered at rate of 2.5 ⁇ l/hour for 28 days. Bars represent the means for the total number of 360° rotations that occurred during a 90 minute testing period that began immediately after the injection of amphetamine [5.0 mg/kg, i.p.].
  • ⁇ p ⁇ 0.05 vs. Transplant+PBS Pregraft mean.
  • t p ⁇ 0.05 vs. Transplant+PBS mean at corresponding time points.
  • FIG. 2 Photomicrographs of coronal brain sections [35 mm] stained for tyrosine hydroxylase (TH), 5 weeks post- transplantation. BDNF or PBS was infused into the caudate-putamen (CP) for 28 days beginning at the time of transplantation.
  • TH tyrosine hydroxylase
  • PBS caudate-putamen
  • FIG. 3 Amphetamine induced rotational behavior before and after surgical implantation of transplants /pumps.
  • Amphetamine induced rotational behavior was assessed 3 weeks after 6-OHDA lesion [Pregraft] and 3, 4, 5, 6, 7, 8, 9, and 10 weeks after transplant/pump surgery.
  • BDNF [3.0 ⁇ g/ ⁇ l] was delivered at a rate of 0.5 ⁇ l/hour for 28 days. Bars represent the mean of the total number of 360° rotations that occurred during a 90 minute testing period that began immediately after the injection of amphetamine [5.0 mg/kg, i.p.].
  • BDNF was delivered at a rate of 1.5 mg/hour for 28 days.
  • Figure 4 Low power photomicrographs of brain sections showing the denvervated/ transplanted striatum (right) in animals receiving infusions of PBS (A) or BNDF (B) in EXAMPLE 2. Sections are in the coronal plane and stained for
  • FIG. D High power photomicrograph of (B) showing transplant and surrounding striatum in a BDNF-infused animal.
  • TH-ir is distributed widely throughout the host striatum, completely filling the region between the graft and the lateral ventricle (V).
  • V lateral ventricle
  • fine TH-ir fibers and punctate granules are diffusely distributed throughout the striatal neuropil, while fascicles of white matter remain unstained.
  • Calibration bar equals 1 mm (A,B) or 375 ⁇ m (C,D).
  • FIG. 5 The extent of outgrowth of TH-ir fibers from the grafts was quantified by subjecting stained brain sections to image analysis. The area of striatal neuropil which contained coarse or fine TH-ir processes was measured on the grafted side. Area measurements were averaged for individual animals within each treatment group, and then a treatment average was calculated using the individual animal averages.
  • the top graph shows the average area of the striatum which contained coarse TH-ir fibers and which clearly projected directly from the transplant into the host striatum. The bottom graph shows the average area of the host striatum occupied by fine, diffusely distributed TH-ir fibers and granules.
  • FIG. 6 Northern blot analysis of BDNF mRNA expression in whole adult rat brain (whole brain) and in the rat striatum at various developmental timepoints. Ten micrograms of total RNA per lane were used for each tissue. The BDNF probe identifies two transcripts (1.6 and 4.0 kb).
  • FIG. 7 Amphetamine induced rotational behavior before and after surgical implantation of transplants/pumps.
  • Amphetamine induced rotational behavior was assessed 3 weeks after 6-OHDA lesion [Pregraft] and 3, 4, 5, 6, 7, 8, 9, and 10 weeks after transplan /pump surgery.
  • Animals were infused with 3.0 ⁇ g/ml of BDNF at a rate of 0.5 ⁇ l/hour directly into the transplant site for a two week period that either began immediately after transplant surgery or was delayed for two weeks following surgery. Bars represent the mean of the total number of 360° rotations that occurred during a 90 minute testing period that began immediately after the injection of amphetamine [5.0 mg/kg, i.p.].
  • Figure 10 Amphetamine-stimulated release of dopamine in denervated / transplanted striatum.
  • the present invention relates to a method of promoting the structural and functional integration of neurons grafted into the central nervous system of a mammal comprising administering a neurotrophic factor to the central nervous system of the mammal, thereby promoting the structural and functional integration of the grafted neurons.
  • the neurotrophic factor is administered to the central nervous system after grafting of the neurons, and during a time period in the ontogenic development of the grafted neurons which corresponds to the time when those neurons, if in their native environment, would normally be exposed to, and would therefore be optimally responsive to, the neurotrophic factor.
  • the neurotrophic factor is selected from the group consisting of NGF, BDNF, NT-3, NT-4/5, and derivatives thereof. In another embodiment, the neurotrophic factor is selected from the group consisting of CNTF, GDNF, and derivatives thereof. In a further embodiment of the invention, at least two neurotrophic factors are administered and are selected from the group consisting of CNTF, GDNF, NGF, BDNF, NT-3, NT-4/5, and derivatives thereof.
  • the grafted neurons are dopaminergic neurons.
  • the dopaminergic neurons may be derived from a mammal of the same species as the graft recipient or from a mammal of a different species as the graft recipient.
  • the dopaminergic neurons are contained in fetal ventral mesencephalic tissue.
  • the recipient mammal is a human and the graft is made to the striatum of the brain as a treatment for Parkinson's disease.
  • dopaminergic neurons could be genetically modified prior to grafting and thus used as carriers for transgenes that endow the grafted cells with properties that may be of therapeutic value.
  • clonal lines of neural progenitor cells, stem cells or lines derived from neurons or their progenitors may be used. Such cells retain at least some of the features of multipotent neural progenitors after transplantation to the brain and therefore would be suitable for intracerebral grafting and in vivo gene transfer to the CNS. (Martinez-Serrano, A., et al., Use of Immortalized Neural Progenitor Cells For Gene Transfer to the
  • ventral mesencephalic tissue obtained from E14 embryos was transplanted to the striata of adult rats in which the endogenous nigrostriatal dopamine system had been previously ablated on the grafted side by injection of 6-hydroxy dopamine (6-OHDA).
  • 6-Hydroxydopamine lesions Male Sprague-Dawley rats (225-250 gm, Harlan Farms) were given unilateral 6- hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway; 6-OHDA (Sigma) was dissolved in 0.9% saline (containing 0.2% ascorbic acid) at a concentration of 2.0 ⁇ g/ ⁇ l and stereotactically injected into the nigrostriatal pathway of anesthetized rats at a rate of 1.0 ml /min for 3 min. Each rat received two injections of 6-OHDA: one in the vicinity of the medial forebrain bundle (AP),
  • Ventral mesencephalic brain regions were dissected from E13-E15 fetuses obtained from timed pregnant female Sprague-Dawley rats (Harlan Farms) and stored separately in a cold, sterile, calcium and magnesium free buffer (CMF: 0.15 M NaCl, 8.0 mM Na2HP04, 2.7 mM KC1, 1.5 mM KHP04, 26.0 mM NaHC03,
  • osmotic pump connector cannula (Plastic Parts Co.) was attached to the free end of the PE 60 tubing extending from the pump and the cannula lowered stereotactically to a point 0.3 mm dorsal to the transplant site.
  • the cannula was permanently affixed to the skull using dental acrylic and anchor screws that were set into the skull earlier during the surgical procedure. At this concentration and flow rate, BDNF was delivered to the transplant site at a nominal rate of 1.875 ⁇ g/hr.
  • BDNF or phosphate buffered saline (PBS) was infused for four weeks into the vicinity of the graft, or into the striata in non-grafted, dopamine depleted control animals.
  • Experimental animals received injections of amphetamine, and asymmetries in locomotor behavior were quantitated as an index of dopamine depletion on the lesioned side relative to the intact side.
  • Rotational Behavior In animals with unilateral lesions of the nigrostriatal pathway, asymmetrical locomotor activity, or rotational behavior, is believed to be a result of a hemispheric imbalance in dopamine release.
  • Amphetamine a potent stimulator of dopamine release, exacerbates the hemispheric imbalance of dopamine release and lesioned animals treated with amphetamine exhibit rotational behavior that is directed away from the intact striatum or, in other words, toward the side of the lesion (ipsilateral rotations), with the number of rotations being directly proportional to the loss of dopamine in the striatum.
  • Treatments which restore dopaminergic activity within the denervated striatum, e.g. neural transplants attenuate the hemispheric imbalance of dopamine release and consequently attenuate amphetamine-induced rotational behavior.
  • Rotational behavior was monitored using the Videomex V image motion computer system (Columbus Instrument, Inc.). Rats were injected with amphetamine [5.0 mg/kg, i.p.] and placed inside opaque, 16 inch diameter cylindrical chambers with flat bottoms. Chambers were situated directly beneath a video camera and multiple animals were monitored simultaneously. The Videomex V system digitized the image of the animal and calculated the total number of 360° clockwise or counterclockwise rotations that occurred during a 90 minute test period.
  • Amphetamine-induced rotational behavior was monitored 1 week before transplant surgery [PREGRAFT] and 3, 4, and 5 weeks after surgery. No differences in rotational behavior were exhibited among the treatment groups prior to transplantation. Lesioned animals receiving chronic infusions of PBS or BDNF, but no transplant, showed no significant attenuation in amphetamine-induced rotational behavior at any time during the five week testing period ( Figure 1). In contrast, animals receiving transplants plus infusions of PBS exhibited the anticipated progressive reduction in ipsilateral rotations over the course of the experiment.
  • Rotational scores were subjected to analysis of variance (ANOVA) with repeated measures using the statistical computer program SuperANOVA (Abacus Concepts).
  • the statistical test comprised one between group measure (TREATMENT) with four different levels of treatment: (1) PBS infusions into deneverated striatum, (2) PBS infusions into transplant sites, (3) BDNF infusions into deneverated striatum, or (4) BDNF infusions into transplant sites.
  • the within variable ( ⁇ ME) comprised 4 repeated measures at the following points:
  • Tyrosine Hydroxylase Immunocytochemis ⁇ ry At the end of the experiment, animals were anesthetised and intracardially perfused with ice cold saline followed by 4% paraformaldehyde. Brains were removed, post-fixed for 24 hours, and then immersed in 30% sucrose. Free- floating brain sections (35 ⁇ m) were immunostained using a monoclonal primary antibody against tyrosine hydroxylase (Chemicon), an avidin-biotin- peroxidase method, (Hsu, S.-M. and Raine, L., J. Histochem. Cytochem. 29:1349-
  • BDNF and PBS were infused as described in the first experiment, except that an osmotic pump with a slower flow rate was used (Alzet 2002 osmotic minipump, 03 ⁇ l/hour).
  • Brain-derived neurotrophic factor was diluted in sterile PBS to a concentration of 3.0 mg/ml and the BDNF solution or PBS alone was loaded into the pump. At this flow rate and concentration, BDNF was delivered into the transplant site at a rate of 1.50 ⁇ g/hr.
  • This dose was selected because it was the smallest amount of BDNF that, when delivered at a flow rate of 0.5 ⁇ l/hr, diffused throughout all or most of the striatum as determined by immunostaining of the exogenously delivered protein. Because the model 2002 pump delivers its contents for only 14 days, the first pump was replaced with a fully loaded second pump at the end of the second week in order to acheive continuous delivery for 28 days. This was accomplished by anesthetizing the animal with a halothane-air mixture (1.5% halothane @ 2.0 1/min), making an incision in the midscapular area, cutting the PE 60 tubing, removing the expired pump, and inserting the second fully-loaded pump into the subcutaneous pocket.
  • a halothane-air mixture (1.5% halothane @ 2.0 1/min
  • the PE 60 tubing attached to the delivery port of the second pump was connected to the severed PE 60 tubing attached to the intracerebral cannula using a small piece of 21 gauge stainless steel tubing. Cyanoacrylate adhesive was applied at the tubing junction, and the incision was closed with metal clips. The second pump was removed using this same procedure three weeks later.
  • Figure 3 shows that ipsilateral rotation was reduced in both PBS and BDNF treatment groups by week 3, consistent with the results from the first experiment. Rotational behavior for PBS treated animals then stabilized, and remained at a relatively constant level for the duration of the study. In contrast, BDNF-treated animals exhibited an overcorrection of the initial (ipsiversive) amphetamine-induced rotational asymmetry, as evidenced by a progressive increase in the rate of contralateral turning during weeks 4, 5, and 6. The rate of contralateral rotation then stabilized, and persisted through week 10, at which time testing was terminated.
  • Both BDNF and PBS infused grafts contained large numbers of TH stained neurons (Figure 4).
  • fiber outgrowth into the host striatum from BDNF-treated grafts was again far more extensive than that observed in transplants exposed to PBS.
  • the enhanced TH immunostaining in the denervated striatum of grafted animals comprised two morphologically distinct forms: long, coarse processes which often could be traced back directly to the grafts, and fine TH-ir fibers and punctate granules which closely resembled the pattern of TH staining normally seen in the intact striatum.
  • SUBSTITUTE SHEET (RULE 25) which could be traced directly from the graft into the host striatum.
  • Density levels were selected to exclude the following from area calculations: TH-ir cell bodies located on the periphery of the graft, fine TH-ir granules and fibers within the host striatum, and background. Low power (2x) images were used to measure fine TH-ir elements distributed diffusely within the host striatum. For fine TH-ir elements, density levels were selected to exclude the following from the area calculations: TH+ cell bodies, densely stained coarse TH+ fibers, and background. All density measurements were made with the observer blind to the treatment.
  • Dopamine release from transplants was measured by placing a microdialysis probe 1 mm adjacent to the transplant site and collecting dialysate samples under condidons of basal and amphetamine-stimulated release. Basal release of dopamine was found to be the same for both PBS and BDNF treated animals (See Lu et al, 1994, Effect of BDNF on fetal mesencephalic grafts: a microdialysis study,
  • BDNF and NT-3 mRNAs in the striata of rats of various ages were determined by Northern blot analysis.
  • Total mRNA was prepared from adult rat brain and from striata dissected from rats of embryonic day 17 (E17), postnatal days 1 (PI), 7 (P7), 14 (P14), and 20 (P20) and adults.
  • Tissue samples were homogenized in 0.3 M LiCl/ 6M urea followed by phenol /chloroform extraction.
  • Ten micrograms of RNA from each sample were electrophoresed on a 1% agarose/ formaldehyde gel, followed by capillary transfer to a nylon membrane (MSI).
  • blots were hybridized overnight at 68°C to either a BDNF probe consisting of a 775 base pair DNA fragment or an NT-3 probe consisting of an 800 base pair DNA fragment labelled with 32 P by random oligo priming (Stratagene) as previously described by P. Maisonpierre, et al., Genomic 10: 559 (1991). Ethidium bromide staining of the gel was used to demonstrate equivalent loading of RNA samples.
  • EIA enzyme-linked immunoassay
  • Striatal tissues were collected at 1, 4, 7, 10, 14, 20, 27, 35, and 45 days after birth from Sprague-Dawley albino rats.
  • BDNF was infused continuously into the transplant site at different two-week intervals following transplantation in order to observe whether or not there existed a critical time period when transplanted fetal dopamine neurons might respond more favorably to an exogenous source of BDNF.
  • the age of the fetal tissue (E14) used in these experiments was approximately 1 week prenatal. Therefore, the actual developmental age of transplanted tissue during each infusion period ranged between: (1) -1 to 1 week postnatal for the 0-2 week post- transplantation infusion period, (2) 2-3 weeks postnatal for the 3-4 week post- transplantation infusion period, and (3) 6-7 weeks postnatal for the 7-8 week post- transplantation infusion period.
  • Ventral mesencephalic tissue obtained from E14 embryos was transplanted to the striata of adult rats in which the endogenous nigrostriatal dopamine system had been previously ablated on the grafted side by injection of 6-hydroxydopamine (6-
  • OHDA OHDA
  • Animals were infused with 3.0 ⁇ g/ml of BDNF at a rate of 0.5 ⁇ l/hour directly into the transplant site for a two week period that either (1) began immediately after transplant surgery or (2) was delayed for two weeks following surgery.
  • the animals received injections of amphetamine, and asymmetries in locomotor behavior were quantitated as an index of dopamine depletion on the lesioned side relative to the intact side.
  • Amphetamine-induced rotational behavior was assessed 3 weeks after 6-OHDA lesion [Pregraft] and 3, 4, 5, 6, 7, 8, 9, and 10 weeks after transplant /pump surgery.
  • Brain-derived neurotrophic factor is known to exert neurotrophic effects upon not only dopaminergic neurons, but also on GABAergic neurons (Hyman, et al., 1994, J. Neurosci. 14: 335-347) and possibly serotonergic neurons.
  • BDNF is known to modulate neuropeptide in both the intact and denervated striatum (Sauer et al., 1994, NeuroReport 5: 609-612). Therefore, it is conceivable that the effects of BDNF on behavior, and more specifically rotational behavior, may also reflect changes in non-dopaminergic systems.

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Abstract

La présente invention concerne un procédé permettant de favoriser l'intégration structurelle et fonctionnelle de neurones greffés à l'intérieur du système nerveux central chez un mammifère, ledit procédé consistant à administrer un facteur neurotrophique au système nerveux central du mammifère, ce qui permet de favoriser l'intégration structurelle et fonctionnelle des neurones greffés. De préférence, le facteur neurotrophique est administré au système nerveux central au cours d'une période du développement ontogénétique des neurones greffés pendant laquelle les neurones sont particulièrement sensibles au facteur neurotrophique. On peut choisir ce facteur neurotrophique dans le groupe constitué du NGF, du BDNF, de NT-3, de NT-4/5 et de leurs dérivés. Une autre possibilité consiste à choisir ce facteur neurotrophique dans le groupe constitué du CNTF, du GDNF et de leurs dérivés. On peut aussi administrer au moins deux des facteurs neurotrophiques appartenant au groupe constitué du CNTF, du GDNF, du NGF, du BDNF, de NT-3, de NT-4/5 et de leurs dérivés. De préférence, les neurones greffés sont des neurones dopaminergiques et sont contenus dans les tissus mésencéphaliques antérieurs foetaux. De préférence, également, le mammifère récepteur est un homme et l'on pratique la greffe au niveau du striatum du cerveau en guise de traitement de la maladie de Parkinson.
PCT/US1996/005814 1995-04-26 1996-04-26 Procedes d'utilisation des facteurs neurotrophiques pour faciliter les greffes de neurones WO1996033731A1 (fr)

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