WO2015107196A1 - Utilisation de thalidomide ou d'analogues de celui-ci pour la prévention de troubles neurologiques induits par une irradiation du cerveau - Google Patents

Utilisation de thalidomide ou d'analogues de celui-ci pour la prévention de troubles neurologiques induits par une irradiation du cerveau Download PDF

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WO2015107196A1
WO2015107196A1 PCT/EP2015/050895 EP2015050895W WO2015107196A1 WO 2015107196 A1 WO2015107196 A1 WO 2015107196A1 EP 2015050895 W EP2015050895 W EP 2015050895W WO 2015107196 A1 WO2015107196 A1 WO 2015107196A1
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compound
cns
radiotherapy
thalidomide
use according
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Franck LEBRIN
Carole SOUSSAIN
Jérémy THALGOTT
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Institut Curie
Centre National De La Recherche Scientifique
INSERM (Institut National de la Santé et de la Recherche Médicale)
College De France
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medicine, in particular oncology and radiotherapy.
  • CNS central nervous system
  • Neurological side effects induced by radiotherapy are classified in three categories: acute (during radiation), early-delayed (up to 6 months post-irradiation) and late-delayed (more than 6 months post-irradiation).
  • Early-delayed complications include somnolence syndrome and transitory cognitive disturbances mainly affecting short-term memory and attention. A preventive role of steroid has been suggested. The severity of these early-delayed complications is not predictive of later, more severe, cognitive impairments.
  • Late-delayed side complications include focal cerebral and spinal cord radionecrosis although they are less likely to occur with more recent irradiation procedure.
  • the most common and serious delayed complication is cognitive dysfunction related to radiation- induced leukoencephalopathy.
  • some patients present a higher risk, especially risk associated with old age, diabetes, high blood pressure, combined radiochemotherapy treatment and presence of a mass. The course is unpredictable; most patients stabilize, some deteriorate slowly, and a few develop severe dementia and eventually die, especially in case of elderly patients. Then, several investigators even recommend to avoid cranial radiotherapy in patient older than 60 years with CNS lymphoma at a risk of a decreased tumor control.
  • the inventors have shown that pericytes are involved in brain response to radiation and that BBB dysfunctions are due to radiation-induced pericyte disengagement. Accordingly, it is hypothesized that it is a primary event preceding cognitive anomalies. The inventors have also demonstrated that thalidomide treatment may prevent radiation treatment induced CNS toxicity.
  • the present invention relates to a compound selected from the group consisting of thalidomide, analogs thereof and pharmaceutically acceptable salts thereof for use for preventing in a patient a CNS complication/injury induced by central nervous system (CNS) irradiation. It also relates to the use of a compound selected from the group consisting of thalidomide, analogs thereof and pharmaceutically acceptable salts thereof for the preparation of a drug for preventing in a patient a CNS complication/injury induced by central nervous system (CNS) irradiation.
  • CNS central nervous system
  • the CNS irradiation is a brain radiotherapy.
  • the compound may present one of the following formulae (I), (II) and (III)
  • Ri is independently selected from -H, -Oi l, -CH 3 , -CH;OZ (ethers ), -CH 2 OCOZ (esters), -CH 2 OCONZ (carbamates ), or -CH 2 Z (alkyls), wherein Z is selected from II or - (CH 2 )n-H, where n is 1 - 10;
  • R5 being selected from the group consisting of pyrazoiidine, tetrazole, and pyrazoline.
  • the compound is selected in the group consisting of thalidomide, lenalidomide, pomalidomide, CC-10015 (Celgene), CC-11006 (Celgene), 3-(5-amino-2-methyl-4-oxo- 4H-quinazolin-3-yl)-piperidine-2,6-dione (Celgene), and pharmaceutically acceptable salts thereof.
  • the compound is selected in the group consisting of thalidomide, lenalidomide, pomalidomide and pharmaceutically acceptable salts thereof.
  • the compound is selected in the group consisting of thalidomide, pomalidomide and pharmaceutically acceptable salts thereof.
  • the compound is pomalidomide or a pharmaceutically acceptable salt thereof.
  • the CNS complication/injury is a late CNS complication/injury. More preferably, the late CNS complication/injury occurs at least six months after the beginning of the CNS irradiation treatment.
  • the CNS complication/injury is a progressive subcortical dementia, especially characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and/or incontinence.
  • the patient has a brain tumor, either a benign brain tumor such as glioma, meningioma, schwannoma, pituitary adenoma, hemanglioblastoma, craniopharyngioma, or preferably a malignant brain tumor such as glioma, glioblastoma, astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, ganglioglioma, mixed glioma, malignant nerve sheath tumor, or brain metastasis of solid tumor or primary CNS lymphoma.
  • a benign brain tumor such as glioma, meningioma, schwannoma, pituitary adenoma, hemanglioblastoma, craniopharyngioma
  • a malignant brain tumor such as glioma, glioblastoma, astrocytoma,
  • the patient is at higher risk of developing a neurological disorder induced by central nervous system (CNS) radiotherapy.
  • CNS central nervous system
  • the patient may be selected among elderly patients, patients with cardiovascular risk, children, especially those of less than 5 years old, adolescents, patients suffering of diabetes or high blood pressure or patients having ApoE polymorphisms (e.g., the presence of the epsilon 4 allele of APOE).
  • the compound can be administered before, simultaneously and/or after the radiotherapy.
  • the compound is to be administered during a period covering one, two, three or four weeks prior the radiotherapy and the radiotherapy duration, and optionally one, two, three or four weeks after the end of the radiotherapy.
  • the compound is to be administered during a period covering one or two weeks prior the radiotherapy and the radiotherapy duration, and optionally one or two weeks after the end of the radiotherapy.
  • the compound is to be administered during 5 to 9 weeks, more preferably 6 to 8 weeks.
  • the daily dose to be administered by oral route is comprised between 0.01 and 500 mg, preferably between 0.1 and 100 mg.
  • the compound is used in combination with an additional therapeutic agent, in particular an antitumoral chemotherapy.
  • an additional therapeutic agent in particular an antitumoral chemotherapy.
  • CNS pericytes are an early target of irradiation.
  • mice model of irradiation inducing late behavioral dysfunctions they have shown that, early after irradiation, pericytes display phenotypic and molecular changes leading to a disruption of their interactions with endothelial cells.
  • pericyte- mediated vascular constriction is altered.
  • Increased blood brain barrier (BBB) permeability is concomitantly observed.
  • thalidomide was proved effective to prevent the radiation-induced pericyte dysfunctions and the increased BBB permeability.
  • the present results demonstrate a pivotal role of pericytes in the radiation-induced CNS toxicity amenable to pharmacological intervention in order to prevent neurological disorders induced by CNS radiotherapy.
  • the present invention relates to a compound selected from the group consisting of thalidomide, analogs thereof and pharmaceutically acceptable salts thereof for use for preventing in a patient a neurological disorder induced by central nervous system (CNS) irradiation, in particular radiotherapy.
  • CNS central nervous system
  • It also relates to the use of a compound selected from the group consisting of thalidomide, analogs thereof and pharmaceutically acceptable salts thereof for the preparation of a medicament for preventing in a patient a neurological disorder induced by central nervous system (CNS) irradiation, in particular radiotherapy.
  • CNS central nervous system
  • CNS central nervous system
  • Thalidomide analogs thereof, pharmaceutically acceptable salt thereof
  • the compounds used in the present invention are thalidomide, analogs thereof and pharmaceutically acceptable salts thereof.
  • lenalidomide also called CC-5013, 3-(4-amino-l-oxo-l,3- dihydro-isoindol-2-yl)-piperidine-2,6-dione
  • pomalidomide also called CC-4047, 4- (amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-l,3-dione
  • the compound is selected from the group consisting of thalidomide, lenalidomide, pomalidomide and pharmaceutically acceptable salts thereof.
  • the compound is selected from the group consisting of thalidomide, pomalidomide and pharmaceutically acceptable salts thereof.
  • the compound is pomalidomide or a pharmaceutically acceptable salt thereof.
  • the compound may be also selected in the following lists: 3,6- dichlorothalidomine, 3,6-diaminothalidomine, 3,6-dihydrazinothalidomine, 5-(amino)-2- (2,6-dioxo-(3-piperidyl))-isoindoline-l,3-dione, 3-(5-amino-2-methyl-4-oxo-4H- quinazolin-3-yl)-piperidine-2,6-dione, CC-10015 (Celgene), CC-11006 (Celgene), ENMD- 0995 (S-3-Amino-phthalimido-glutarimide or S-3APG), CPS11, CPS45,
  • the preferred thalidomide analogs could be defined by the following one of the following formulae (I), (II) and (III)
  • Ri is independently selected from -H, -Oi l, -CH 3 , -CH 2 OZ ( ethers ), -CH 2 OCOZ (esters), - CH 2 OCONZ (carbamates ), or -CH 2 Z (alkyls), wherein Z is selected from I I or - ( CH : ),,-! I, where n is 1 - 10;
  • R3 is selected from -I I. Ci-Cg alkyl. benzyl or halogen;
  • Ri is -H.
  • R 2 is -H or -NH 2 .
  • R x is preferably -I I, -F, -CI, -CM 3 or benzo. in particular -H. -F. or -CI 13. In a preferred embodiment. R is -I I.
  • R 4 is I I.
  • the pharmaceutically acceptable salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like.
  • Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002.
  • the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate.
  • Thalidomide and its analogs, Lenalidomide and Pomalidomide, are used in the treatment of hematologic malignancies, especially multiple myeloma.
  • Lenalidomide has also been developed for the treatment of myelodysplasia syndromes (MDS). It is undergoing clinical trial as a treatment for Hodgkin's lymphoma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia.
  • Thalidomide and its analogs could present a therapeutic advantage in order to prevent radiation induced neurocognitive disorders.
  • RTOG 0118 relating to randomized patients with multiple brain metastases treated by radiotherapy with or without thalidomide
  • the authors reported that the neurocognitive decline induced by radiotherapy is not significantly different when patients are treated with thalidomide (Corn et al, 2008, Int J Radiation Oncology Biol Phys, 1, 71-78).
  • thalidomide when used in association with radiotherapy for the treatment of brain tumors (i.e., brain stem gliomas and glioblastomas).
  • brain tumors i.e., brain stem gliomas and glioblastomas.
  • the scientific literature always discloses treatments with thalidomide or analogs thereof in which the highest tolerable dosage is used and the treatment durations are long (i.e., several months). More specifically, in the above- mentioned clinical trials, thalidomide is given from the first day of radiotherapy up to several months after its end with a dose escalation up to 1,200 mg/day.
  • thalidomide and its analogs could be used for preventing radiation induced toxicity, in particular for preventing neurological disorders induced by central nervous system (CNS) radiotherapy. More specifically, the inventors defined that thalidomide and its analogs can have advantageous effects for preventing radiation induced toxicity when used with short period of treatment, especially when compared with the very long period tested in the prior art (e.g., several months, more frequently one year or more). This short treatment period allows to obtain therapeutic benefits while avoiding the well-known possible side effects of thalidomide and its analogs. More preferably, the treatment period begins before CNS radiotherapy.
  • the CNS complication/injury affects in particular the cognitive functions.
  • Cognitive functions can be impaired. Severe cases result in a subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and/or incontinence. Lethargy, focal deficits, seizure can be associated. More particularly, the cognitive dysfunction is related to radiation-induced leukoencephalopathy. Pathological findings include vascular lesions such as stenosis, thrombosis, haemorrhage, fibrinoid vascular necrosis, and demyelination. However, the present invention may also concern spinal cord radiotherapy. In this context, the complication is rather myleopathy.
  • the CNS complication/injury concerns late complications, such as delayed cognitive impairment.
  • Late CNS complication/injury occurs at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 months after the beginning of the CNS irradiation treatment.
  • late CNS complication/injury occurs at least 3, 4, 5, 6, 7, 8, 9, 10 months after the beginning of the CNS irradiation treatment.
  • late CNS complication/injury occurs at least 5, 6, 7 months after the beginning of the CNS irradiation treatment.
  • late CNS complication/injury occurs at least 6 months after the beginning of the CNS irradiation treatment.
  • late CNS complication/injury occurs at least 3 months after the beginning of the CNS irradiation treatment.
  • the present invention relates to CNS or brain tumor, either a benign brain tumor such as glioma, meningioma, schwannoma, pituitary adenoma, hemanglioblastoma, craniopharyngioma, or preferably a malignant brain tumor such as glioma, glioblastoma, astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, ganglioglioma, mixed glioma, malignant nerve sheath tumor, or brain metastasis of solid tumor or primary CNS lymphoma.
  • the brain tumor is a malignant one.
  • it relates to CNS or brain tumors that can be treated by radiotherapy, alone or combined with chemotherapy.
  • the CNS or brain tumor is a primary CNS lymphoma.
  • the patient is a human being. He could be a child, an adolescent, an adult, even an elderly subject. By elderly subject is intended a person of 60 years old or more.
  • the patient is a human being of 60 years old or older.
  • the patient is a human being of 65 years old or older, more preferably, a human being of 70 years old or older.
  • the patient presents an increased risk of radiation-induced CNS complications/injuries.
  • the patient can be selected in the group consisting of a child, in particular a child of less than 5 years old, an adolescent, a elderly subject, patients at cardiovascular risk, patients suffering of diabetes or high blood pressure and patients having APOE polymorphisms.
  • APOE polymorphisms have been described a factor increasing the risk of CNS complication/injury, in particular the presence of the epsilon 4 allele of APOE (Ahles el al. Psychooncology. 2003, 12(6):612- 9).
  • the risk also depends on the volume of the brain tissue to be treated, the total irradiation dose, and the fractionation schedule.
  • the CNS irradiation treatment is the first line of treatment of the patient.
  • the patient has not been previously treated by radiotherapy, in particular CNS irradiation treatment, by chemotherapy or by the combination of radiotherapy and chemotherapy.
  • the patient did not relapse since his former line of treatment and/or the patient's condition is stable for at least 1, 2, 3, 4, 5 or 6 months prior to the CNS irradiation treatment.
  • the patients can also be a non-human mammal such as pets, horses, or farm animal. Therefore, the veterinary use of the invention is also contemplated.
  • Irradiation includes therapeutic irradiation of the CNS and accidental irradiation.
  • Therapeutic irradiation of the CNS also referred to as CNS radiotherapy, includes but is not limited to ⁇ -rays or X-rays radiotherapy, preferably X-rays radiotherapy.
  • Therapeutic irradiation can be applied by external beam radiation therapy, by brachytherapy or systemic radioisotope therapy.
  • CNS radiotherapy is selected from the group X- rays radiotherapy applied by external beam radiation therapy.
  • the present invention relates to CNS radiotherapy. More specifically, it relates to brain radiotherapy. Alternatively, it may also relate to spinal cord radiotherapy.
  • a total safe dose of irradiation e.g. 40-60 Gy
  • the total safe dose is applied as daily fractions in order to avoid radiation induced injury, usually 4-7 fractions a week, for instance fractions of less than 2 Gy, in particular of 1.8-2.0 Gy.
  • EBRT external beam radiation therapy
  • 3D-CRT Three-dimensional conformal radiation therapy
  • IMRT Intensity modulated radiation therapy
  • Conformal proton beam radiation therapy or Stereotactic radiosurgery/stereotactic radiotherapy.
  • the radiotherapy can be used in combination with an antitumoral agent such as therapeutic antibody, bevacizumab, everolimus, rituximab, or with a chemotherapeutic agent.
  • an antitumoral agent such as therapeutic antibody, bevacizumab, everolimus, rituximab, or with a chemotherapeutic agent.
  • the chemotherapy is carried out before the radiotherapy, especially in case of primary CNS lymphoma.
  • the chemotherapeutic agent is methotrexate.
  • the chemotherapy can be carried out simultaneously with the radiotherapy, especially in case of glioblastoma.
  • the chemotherapeutic agent is temozolomide.
  • Thalidomide the analogs thereof or the pharmaceutical salts thereof can be administered prior, simultaneously or concomitantly and/or after radiotherapy.
  • duration of treatment with thalidomide, the analogs thereof or the pharmaceutical salts thereof is relatively short. Duration of less than 8, 7, 6, 5, 4, 3, 2 or 1 weeks is contemplated. For instance, duration comprised between 1 and 8 weeks is contemplated, preferably between 2 and 6 weeks, more preferably between 3 and 4 weeks. A single period or cycle of treatment is contemplated.
  • Thalidomide or analog or salt thereof is to be administered during a period covering one, two, three or four weeks prior the radiotherapy and the radiotherapy duration, and optionally one, two, three or four weeks after the end of the radiotherapy.
  • the treatment period may begin between one and two weeks before the beginning of the radiotherapy, more preferably about one week before.
  • the treatment period include the period of radiotherapy, especially when fractioned radiotherapy is chosen.
  • the treatment is carried on after the end of radiotherapy, in particular during a period of between one and four weeks, in particular about 1, 2, 3, or 4 weeks. More preferably, the period of treatment after the radiotherapy lasts one or two weeks.
  • Thalidomide the analogs thereof or the pharmaceutical salts thereof can be administered by any convenient route.
  • it can be administered by oral route (in the form of discrete units as capsules, sachets, tablets or lozenges) or by systemic route, for instance subcutaneous, intravenous injection or infusion.
  • terapéuticaally effective amount it is meant the quantity of the composition of the invention which prevents, removes or reduces the CNS complication/injury in mammals, including humans. It is understood that the administered dose may be adapted by those skilled in the art according to the patient, the pathology, the mode of administration, etc.
  • a daily dose, by oral route can vary and could be comprised between 0.01 and 500 mg, preferably between 0.01 and 100 mg or 0.1 and 100 mg, more preferably between 0.01 and 50 mg and even more preferably between 0.1 and 50 mg.
  • a daily dose, by oral route can vary and could be comprised between 0.01 and 40 mg, preferably between 0.01 and 25 mg, more preferably between 0.01 and 10 mg, and even more preferably between 0.1 and 10 mg.
  • a daily dose of thalidomide can be comprised between 50 and 500 mg, preferably between 100 and 300 mg, still more preferably between 150 and 250 mg.
  • a daily dose of thalidomide can be comprised between 1 and 500 mg, between 1 and 200 mg, between 1 and 150 mg, between 1 and 50 mg and even more preferably between 1 and 25 mg.
  • a daily dose of lenalidomide can be comprised between 1 and 50 mg, preferably between 5 and 30 mg, more preferably between 0.1 and 30 mg, still more preferably between 5 and 30 mg, and even more preferably between 10 and 25 mg.
  • a daily dose of pomalidomide can be comprised between 0.01 and 10 mg or between 0.1 and 10 mg, preferably between 0.01 and 15 mg, more preferably between 0.1 and 10 mg, still more preferably between 1 and 7 mg, and even more preferably between 3 and 5 mg.
  • low doses can be used, in particular 80, 70, 60 or 50 % of the above mentioned daily dose.
  • FIG. 1 Characterization of the radiation-induced model of toxicity on the central nervous system Irradiation was delivered to the whole brain excluding the eyes and the olfactory bulb at doses ranging from 10 to 40 Gy, to 5-6 8-weeks old mice for each dose level, a. Weight curves represent the median of weight variations from baseline for each dose level after irradiation, b. Survival curves in each group. Mice were sacrificed between 136 and 139 days after irradiation, right after the activity tests, c-d. Activity tested 4 months after increasing doses of irradiation. Results were obtained from 5-6 mice in each group, c. To perform the stand up test, mice were observed for 5 min and the observer counted every stand up position, d.
  • mice were placed in the center on the horizontal part of a hanger and the observer recorded the time till the mice fell. Values are given as means + s.e.m. *P ⁇ 0.05, and **P ⁇ 0.01, results from unpaired t test.
  • FIG. 4 Pericyte-mediated vessel constriction
  • FIG. 5 Pericyte-mediated vessel constriction is impaired in irradiated mice, an effect reversed by pharmacological treatment with thalidomide, a-d.
  • Graphs Distribution of the proportion of arteriolar vessels (left graph) and arteriolar capillaries (right graph) that constricts according to the intensity used to stimulate pericyte contraction. An average of 15 pericytes were stimulated per retina and between 4 to 7 mice were used per condition, e. Percent of pericytes that is able to induce an arteriolar vessel constriction at 1.5 ⁇ . f. Percent of pericytes that is able to induce an arteriolar capillary constriction at 2.0 ⁇ . *P ⁇ 0.05, **P ⁇ 0.01 and ***P ⁇ 0.001, ****P ⁇ 0.0001, Chi- square test. 95 % CI
  • FIG. 6 The radiation-induced blood-brain barrier permeability is prevented by Thalidomide.
  • Mice were euthanized 8 days after irradiation.
  • Thalidomide was administered as intraperitoneal injection (150 mg/kg body weight per injection on days -7, -5, -2, +3 and +6 from irradiation).
  • Vehicle (DMSO) was administered on the same days than thalidomide in control and irradiated animals.
  • Cadaverin Alexa-Fluor-555 was injected intravenously as a tracer of vasculature permeability, a.
  • Example 1 Thalidomide prevents radiation-induced CNS toxicity by inhibiting pericyte disengagement from endothelium
  • mice To study the effect of radiation on the CNS pericytes, the inventors set up an in vivo model of CNS irradiation in mice. Single fractions of irradiation delivered to the brain of adult mice, at doses ranging from 10 to 30 Gy, did not affect weight or survival of mice during 5 months follow up (Fig 1 a-b). Four months after irradiation, mice that had received at least 20 Gy exhibited a lower score on basic motor activity tests (stand up and traction tests) (Fig lc-d)).
  • the inventors took advantage of the vasculature of the retina as a surrogate site of the CNS because the eye is anatomically an extension of the CNS, it is a well-described model for analyzing pericyte-endothelial cells interactions, and finally because both CNS and retina vasculatures are the most pericyte-covered organs. They tested increasing doses of irradiation delivered to the eyes ranging from 15 to 25 Gy and observed a change of the pericytes phenotype at the 20 Gy level. As expected, TGF- ⁇ and Notch signaling pathways were activated in isolated retinas. Indeed, N-cadherin RNA and the Notch target gene Hey 1 were over expressed in retina nine days after irradiation at the dose of 20 Gy (Fig le-f). The radiation dose of 20 Gy was thus selected for further experiments.
  • the inventors first investigated structural changes in pericytes of the retina occurring early after irradiation of mice and then tested the effects of thalidomide given before (days -7, -5, -2) and after (days +3 and +6) irradiation.
  • Pericytes and ECs interacts in the neuro-vascular unit for the regulation of blood flow in arterioles and capillaries, in response to changes in neural activity.
  • the contractile property of pericyte can be measured on ex vivo retina.
  • an electrical stimulation is applied with a pipette pressed on the pericyte soma, it induces a pericyte contraction that in turn mediates the underlying vessel constriction (Peppiatt et al, 2006, Nature, 443, 700-704), which requires a close interaction between pericyte and EC.
  • the alteriolar capillaries were identified by a positive reactivity with the cc-SMA immunostaining and a weaker positivity for the connexin 40, and a median diameter of arteriolar capillaries of 23 pixels (range, 11-39).
  • a 2 ⁇ electric current applied on pericytes induced the contriction of most of the arteriolar capillaries.
  • Venous capillaries, negative for con40 and CC-SMA immuno staining were unresponsive to electrical stimulation of pericytes.
  • Proportions of contractile pericytes in control, RT, RT+ Thai and RT+Thal+STI-571 were 75%, 29 %, 64 %, and 54 % respectively (p ⁇ 0.0001, Chi-square 95 % CI), although the difference between RT + Thai and RT+Thal+STI-571 did not reach statistical significance (fig 5e-f).
  • the inventors deemed these radiation-induced consequences on pericytes and pericytes-ECs interactions to result in in vivo deregulation of the arteriolar and capillary blood flow, which may contribute to late radiation-induced brain damages.
  • cadaverine Alexa Fluor-555 as a fixable tracer (950 D).
  • the fluorescent dye cadaverine Alexa Fluor- 555 significantly extravasated in the retina and in the brain parenchyma of irradiated mice (fig. 6a, b, d)) but not in control mice.
  • Extravascular Cadaverine Alexa Fluor-555 localized mainly to neurons (fig 6c). No leakage of the tracer was observed when thalidomide was administered to irradiated mice.
  • mice Experiments were done on adult mice (8 to 12 weeks old). The inventors took advantage of NG2DsRedBAC-transgenic mice, which express the red fluorescent protein (DsRed) under the control of the Cspg4 (encoding NG2) promoter Zhu, et al, 2008, Development, 135, 145-157).
  • DsRed red fluorescent protein
  • Cspg4 encoding NG2 promoter Zhu, et al, 2008, Development, 135, 145-157.
  • experiments were done on C57/BL6 adult male. Groups of 3 to 10 mice were constituted for each experiment. Mice were bred under isolator condition and maintained in filtered-top microisolator cages. Food and water were provided ad libitum. The local welfare committee approved experimental protocols. Mice were killed by quick elongation.
  • mice were immobilized in a containment device without anesthesia.
  • the heads of adult mice were exposed to a X-ray generator Philips/YXYLON type MG325 (200 kV voltage, 21 mA intensity), the X-ray beam was collimated by a bloc of lead located at 50 cm from the source.
  • Four mice were irradiated by run. A total dose of 20 Gy was delivered in a single fraction at a dose rate of 0.9 Gy/min. Dosimetry was performed on 4 mice.
  • irradiation was confined to the brain. Mice were anesthesized with inhalational isofluorane.
  • mice were exposed to a X-ray generator Xrad320 (PXI) (200 kV voltage, 20 mA intensity). Mice were individually irradiated. A total dose of 20 Gy was delivered in a single fraction at a dose rate of 0.97 Gy/min by two lateral beams. The irradiation field was a 2x2.5 cm 2 rectangular field. Dosimetry was performed on 4 mice.
  • PXI X-ray generator Xrad320
  • Thalidomide ((+)-2-(2,6-Dioxo-3-piperidinyl)-lH-isoindole-l, 3(2H)-dione) was synthetized par Green Parma. Thalidomide was diluted in dimethylsulfoxyde (DMSO) (95 mg/ml). Mice received intraperitoneal injection of vehicle (DMSO) or thalidomide (150 mg/kg) on days -7, -5, -2, +3 and +6 from irradiation. STI-571 (Gleevec) was purchased from euromedex (#S2475) and diluted in water. Mice received intraperitoneal injection of 150 ⁇ vehicle or gleevec (50 mg/kg) on the same days as thalidomide.
  • DMSO dimethylsulfoxyde
  • STI-571 (Gleevec) was purchased from euromedex (#S2475) and diluted in water. Mice received intraperitoneal injection of 150
  • biotinylated Isolectin B4 Invitrogen
  • rabbit anti-mouse Ki67 cat # 66155, Abeam
  • rabbit anti-mouse cleaved caspase 3 cat # 9664, Cell signaling
  • FITC-anti alpha smooth muscle antibody ccSMA
  • Rat anti-mouse CD31 cat # 553370 BD Bioscience
  • rabbit anti-mouse Glut 1 cat # 07- 1401, Millipore
  • rat anti-mouse collagen IV cat # 2150-1470, AbD Serotec.
  • Specimen were analyzed with a confocal laser-scanning microscope inversed-SP5 (Leica). Confocal images of Immunohistochemistry results are presented as 3D reconstructions of z-stacks.
  • pericytes were patched with pipette filled with the same solution. Resistance of the pipette was measured before each experiment in order to define the input voltage (pulses 0.02 ms, 10 Hz for 5 s) to be applied so as to deliver a current intensity increasing from 1 to 7 ⁇ .
  • Pericytes were stimulated by applying voltage pulses 20 secondes after the patch. A total of 300 images was recorded in 2.5 minutes.
  • primers were used: for mouse PDGFR- ⁇ (QTOOl 13148); for PDGF- ⁇ , primer set (QT00266910); for Cspg4 (NG2), primer set (QT00120407) NG2; for cc-SMA, primer set (QT0088102); for RGS-5, primer set (QT00102592); for Desmine, primer set (QT00102333); for ALK5, primer set (QT100034117); for N-Cadherin, primer set (QT00148106); for Heyl, primer set (QT 00115094); for Hes, primer set (QT00313537); for Jag 1, primer set (QTOOl 15703); for VE-cadherin, primer set (QT00595840).
  • the data were normalized to a reference pool including mouse GAPDH and HPERT. Fold changes were calculated using the comparative CT method.
  • the goal of this study is to analyze the social behavior of mice through a social interaction test. This test is based on a test designed by Cambon K et al (Neuroscience, 2010, 171 (3), 840-51).
  • mice In total, 80 mice are needed for this experiment, 40 are to be tested (4 groups of 10 mice) and 40 are used as interaction partners.
  • the 4 groups are the followings: Group 1 without irradiation and thalidomide; Group 2 without irradiation but with thalidomide; Group 3 irradiated without thalidomide; Group 4 irradiated with thalidomide.
  • mice to be tested are isolated (individual cages) for 3 weeks. However, the interaction partner mice are raised in social cages.
  • the mouse to be tested is introduced in a new and neutral environment (a Plexiglas cage) for 30 minutes. Then, a second mouse (the interaction partner), raised in social conditions, is introduced. The test lasts 8 minutes and begins when the mice are put in presence of each other. The second mouse has to be unknown from the first and to share the same genotype. The interactions between the 2 mice are filmed during 8 minutes.
  • the social behavior is analyzed manually and only the first 4 minutes are to be analyzed.
  • the analysis is done by a behavioral specialist.
  • the experimenter in charge of the experiments works in a blind manner (without knowing to which group the animals belong).
  • the goal of this study is to analyze the spatial working memory abilities of mice for a spontaneous alternation task in a T labyrinth. This test is based on a test designed by
  • mice 40 mice are needed for this experiment (4 groups of 10 mice, the same than Example 2).
  • the Period of habituation to the dispositive includes labyrinth habituation, opening and closing of the doors of the dispositive habituation.
  • (ITI) time are variable but fixed: 5 sec, 30 sec or 120 sec.
  • the experimenter in charge of the experiments works in a blind manner (without knowing to which group the animals belong).
  • mice The goal of this study is to analyze the long-term memory abilities of mice in an object memory task. This test is based on a test designed by Wilkund A et al (Neuroreport, 2009, 20 (16), pp 1419-23).
  • mice 40 mice are needed for this experiment (4 groups of 10 mice, the same than Example 2). Each mouse is subjected to a protocol including several successive conditions: dispositive habituation, being put in presence of 2 objects, being put in presence of a new object.
  • mice to be tested have a period of dispositive habituation before testing. Then, they are subjected to the memory object test: 3 sessions of 5 minutes with 2 identical objects, then, 24 hours later, a session with a new object.
  • the experimenter in charge of the experiments works in a blind manner (without knowing to which group the animals belong).
  • the following parameters are studied: - Contact time with objects.

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Abstract

La présente invention concerne l'utilisation de thalidomide ou d'analogues de celui-ci pour la prévention de troubles neurologiques induits par une irradiation du cerveau.
PCT/EP2015/050895 2014-01-20 2015-01-19 Utilisation de thalidomide ou d'analogues de celui-ci pour la prévention de troubles neurologiques induits par une irradiation du cerveau WO2015107196A1 (fr)

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US9732064B2 (en) 2006-09-26 2017-08-15 Celgene Corporation 5-substituted quinazolinone derivatives and compositions comprising and methods of using the same
US9751853B2 (en) 2011-03-11 2017-09-05 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
WO2019089993A1 (fr) * 2017-11-02 2019-05-09 Living Cell Technologies New Zealand Limited Agents protecteurs de péricytes pour troubles neurologiques comprenant les maladies neurodégénératives, les maladies du système nerveux central et autres
US10414755B2 (en) 2017-08-23 2019-09-17 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US10844039B2 (en) 2018-11-13 2020-11-24 Biotheryx, Inc. Substituted isoindolinones
CN113499341A (zh) * 2021-06-30 2021-10-15 中山大学孙逸仙纪念医院 沙利度胺在制备用于治疗放射性脑损伤的药物中的应用
US11185537B2 (en) 2018-07-10 2021-11-30 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US11192877B2 (en) 2018-07-10 2021-12-07 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US11548870B2 (en) 2019-11-19 2023-01-10 Bristol-Myers Squibb Company Compounds useful as inhibitors of helios protein
US11718601B2 (en) 2021-04-06 2023-08-08 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds

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Cited By (17)

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US9732064B2 (en) 2006-09-26 2017-08-15 Celgene Corporation 5-substituted quinazolinone derivatives and compositions comprising and methods of using the same
US9751853B2 (en) 2011-03-11 2017-09-05 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
US9969713B2 (en) 2011-03-11 2018-05-15 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
US9682952B2 (en) 2012-09-04 2017-06-20 Celgene Corporation Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl) piperidine-2-6-dione and methods of preparation thereof
US11053218B2 (en) 2017-08-23 2021-07-06 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US10414755B2 (en) 2017-08-23 2019-09-17 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US10640489B2 (en) 2017-08-23 2020-05-05 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US10647701B2 (en) 2017-08-23 2020-05-12 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2019089993A1 (fr) * 2017-11-02 2019-05-09 Living Cell Technologies New Zealand Limited Agents protecteurs de péricytes pour troubles neurologiques comprenant les maladies neurodégénératives, les maladies du système nerveux central et autres
US11192877B2 (en) 2018-07-10 2021-12-07 Novartis Ag 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US11185537B2 (en) 2018-07-10 2021-11-30 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US11833142B2 (en) 2018-07-10 2023-12-05 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US10844039B2 (en) 2018-11-13 2020-11-24 Biotheryx, Inc. Substituted isoindolinones
US11352338B2 (en) 2018-11-13 2022-06-07 Biotheryx, Inc. Substituted isoindolinones
US11548870B2 (en) 2019-11-19 2023-01-10 Bristol-Myers Squibb Company Compounds useful as inhibitors of helios protein
US11718601B2 (en) 2021-04-06 2023-08-08 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds
CN113499341A (zh) * 2021-06-30 2021-10-15 中山大学孙逸仙纪念医院 沙利度胺在制备用于治疗放射性脑损伤的药物中的应用

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