+ All Categories
Home > Documents > Infectia Cu Virus Herpetic a Creierului

Infectia Cu Virus Herpetic a Creierului

Date post: 01-Jun-2018
Category:
Upload: cristian-ionut
View: 253 times
Download: 0 times
Share this document with a friend

of 42

Transcript
  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    1/42

    H ERPES S IMPLEX VIRUSINFECTIONS OF THE BRAIN:

    F ROM ENCEPHALITIS TO GENETHERAPY

    RJ Whitley(USA)

    1999 The International Herpes Management Forum, all

    rights reserved .

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    2/42

    VIRAL GENE TRANSFER SYSTEMSVIRAL GENE TRANSFER SYSTEMS

    Retroviruses

    Adenovirus

    Adeno-associated virus (AAV)

    Herpes simplex virusVaccinia virus

    Polio virus

    Sindbis and other R A viruses

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    3/42

    HERPES SIMPLEX ENCEPHALITISHERPES SIMPLEX ENCEPHALITIS

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    4/42

    OUTCOME OF PATIENTS WITH HSEOUTCOME OF PATIENTS WITH HSENO OR INEFFECTIVE THERAPY NO OR INEFFECTIVE THERAPY

    %Patients

    Mo ta!it" Mo #i$it" S& 'i'o s

    ())*ea$

    Se'e e

    Mo$e ate

    No +a! Mi!$

    ,)-).)

    /)0)1)2)3)

    ())

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    5/42

    WHY AN HSV VECTOR4WHY AN HSV VECTOR4

    eurovirulent

    Recombinants!revertants

    P os

    "ar#ets neuronal tissue

    $an remove neurovirulence #ene(s)% & thymidine 'inase

    & *+,

    ar#e codin# capacity

    Cons

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    6/42

    GENETICALLY ENGINEERE* HSV:GENETICALLY ENGINEERE* HSV:POSSIBLE APPLICATIONSPOSSIBLE APPLICATIONS

    Attenuated vaccine

    "umor therapy (i+e+ #lioblastoma) .orei#n #ene expression

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    7/42

    HSV THERAPY OF BRAIN TUMORS:HSV THERAPY OF BRAIN TUMORS:HISTORY HISTORY

    (,0) % Passa#ed /ild-type viruses retainvirulence 0or surroundin# normal brain tissue(,,( % "hymidine-'inase ne#ative virus lac'ssi#ni1cant oncolytic activity(,,3 &(,,/ % HSV deletions in ( *+, #enestudied 0or sa0ety and e2cacy(,,- % Human trials

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    8/42

    HSV5( GENOMEHSV5( GENOME

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    9/42

    ( 2160 Gene2160 Gene

    ocated in the inverted lon# repeats o0 the 3 L se#ment4iploid #ene5 re#ulated as a #ene67$ rich5 promoter located in the 8a9 se:uenceProtein product is ;< aa lon#5 molecular /ei#ht* =4a$onsists o0 a lar#e amino terminus domain ( ,>aa)? a lin'er!s/ivel re#ion o0 aa Ala-"hr-Pro

    repeated @ times? and a carboxy terminaldomain o0 *aa

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    10/42

    FUNCTIONS OF THEFUNCTIONS OF THE ( 2160 GENE2160 GENE

    *+, #ene encodes 0or the neurovirulence o0 HSVViruses de0ective in *+, #ene re:uire anincrease in

    dose over /ild type virus to 'ill animals byintracerebralor peripheral inoculationViruses de0ective in *+, #ene have diminshedcapacity to establish latency and be reactivated

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    11/42

    ABLATION OF HSVABLATION OF HSVNEUROVIRULENCENEUROVIRULENCE

    VIRUSHSV- (.)4eletion o0 ( *+,Stop codon insert

    into *+,HSV- (.) repaired

    PFU L* 0)@@@

    B @@@ @@@B @ @@@ @@@

    @@

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    12/42

    MALIGNANT GLIOBLASTOMAMALIGNANT GLIOBLASTOMA

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    13/42

    CENTRAL NERVOUS SYSTEMCENTRAL NERVOUS SYSTEMTUMORSTUMORS

    Cali#nant #liomas are the most common $ StumorB ,?@@@ ne/ cases annually (3SA)

    "herapies & cytoreductive? radiation?chemotherapy &have not chan#ed outcomeCedian survival is year

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    14/42

    EXPERIMENTAL MURINE MO*ELEXPERIMENTAL MURINE MO*EL

    Human tumors studied in mice that haveno eDective immune response (S$E4 mice)Emmune competent mice studied 0orcyto'ine expression to document immuneresponse

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    15/42

    BRAIN TUMOR MO*ELSBRAIN TUMOR MO*ELS

    Entracranial% S$E4 mice& C", >C6 (mouse)

    & 3;, C6 (human)

    & 4,*C6 (human)Entracranial% immune competent mice & 6 ;< (mouse)EnFect cells? establish tumor (, days)? inoculate vector

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    16/42

    HUMAN TUMOR 7*01MG8 IN SCI*HUMAN TUMOR 7*01MG8 IN SCI*MOUSEMOUSE

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    17/42

    HISTOPATHOLOGY OF *01MGHISTOPATHOLOGY OF *01MGTUMOR IN SCI* MOUSETUMOR IN SCI* MOUSE

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    18/42

    HSV R1)), TREATMENT OF *01MG5HSV R1)), TREATMENT OF *01MG5BEARING SCI* MIICEBEARING SCI* MIICE

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    19/42

    HSV R1)), TREATMENT OFHSV R1)), TREATMENT OFU30(MG5BEARING SCI* MICEU30(MG5BEARING SCI* MICE

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    20/42

    ABSENCE OF TUMOR IN LONG5TERM SURVIVORSABSENCE OF TUMOR IN LONG5TERM SURVIVORS

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    21/42

    HSV THERAPY OF HUMAN TUMORSHSV THERAPY OF HUMAN TUMORSIN SCI* MICE: SUMMARY IN SCI* MICE: SUMMARY

    Survival prolon#edon#-term survivors are disease 0reeHSV 4 A detected by P$R in brain

    tissue$an /e do betterG

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    22/42

    FOREIGN GENE EXPRESSION IN HSV:FOREIGN GENE EXPRESSION IN HSV:RATIONALERATIONALE

    o sin#le modality o0 therapy has proven to beeDective3nli'ely to be able to inFect enou#h virus to

    in0ect all tumor cells.orei#n #ene expression could%& modulate immune response& introduce en ymes to activate prodru#s& introduce tumor suppressor #enes

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    23/42

    SELECTE* CYTO9INE GENESSELECTE* CYTO9INE GENES

    Inse t E e;tsE -; Re#ulates "h cellsE -* Re#ulates "h; cells? I cells? and

    macropha#es? enhances diDerentiation o0

    " cells and promotes anti#lioma eDectsE -, Emmune-enhancementE - @ 4o/n re#ulates "h cyto'ine expression?

    promotes tumor #ro/th

    SCHEMATIC *IAGRAM OFSCHEMATIC *IAGRAM OF 21602160 HSVHSV

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    24/42

    SCHEMATIC *IAGRAM OFSCHEMATIC *IAGRAM OF (( 21602160 HSVHSVEXPRESSING INTERLEU9INSEXPRESSING INTERLEU9INS

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    25/42

    HSV CYTO9INE EXPRESSIONHSV CYTO9INE EXPRESSION ININVITROVITRO

    C"to

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    26/42

    HSV5INTERLEU9IN TREATE* C0.BL /HSV5INTERLEU9IN TREATE* C0.BL /MICE BEARING GL53/( GLIOMASMICE BEARING GL53/( GLIOMAS

    IMMUNE5RELATE* INFLAMMATORY CELLSIMMUNE5RELATE* INFLAMMATORY CELLS

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    27/42

    IMMUNE5RELATE INFLAMMATORY CELLSIMMUNE5RELATE INFLAMMATORY CELLSINFILTRATING GL53/( GLIOMAS IN C0.BL /INFILTRATING GL53/( GLIOMAS IN C0.BL /

    MICE . *AYS AFTER HSV THERAPY MICE . *AYS AFTER HSV THERAPY

    T>e a?" C*1@ C*-@Ma; o?>a es

    T ;e!!s T ;e!!s

    Saline @+, L + L + + L*+;

    R < < *+K L, @+; 7*+; >+; L,

    RK @< ; + L*+K ; +K L*+*(E -*)

    RK @K *+K L + +K 7 + +K L

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    28/42

    HISTOPATHOLOGIC CHANGES FOLLOWHISTOPATHOLOGIC CHANGES FOLLOWHSV CYTO9INE EXPRESSION IN TUMORSHSV CYTO9INE EXPRESSION IN TUMORS

    7216058 IL51 IL5()

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    29/42

    PRIMUM NON NOCEREPRIMUM NON NOCERE

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    30/42

    HUMAN GLIOBLASTOMAHUMAN GLIOBLASTOMA

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    31/42

    PHASE ( TRIAL OF GENETICALLY ENGINEERE*PHASE ( TRIAL OF GENETICALLY ENGINEERE*HSV: THERAPY OF GLIOBLASTOMAHSV: THERAPY OF GLIOBLASTOMA

    $onstruct% 6;@ac's both copies o0 *+,Ribonucleotide reductase #ene

    mutated /ith acM insertion$annot replicate in post-mitotic cells(e+#+ neurons)

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    32/42

    PRE5CLINICAL SAFETY OF G53).PRE5CLINICAL SAFETY OF G53).

    6enetic stability% miceatency and reactivation% mice and rabbitseurovirulence% Aotus nancymai

    VAGINAL INOCULATION OF WIL*5TYPE ORVAGINAL INOCULATION OF WIL*5TYPE OR

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    33/42

    VAGINAL INOCULATION OF WIL*5TYPE ORVAGINAL INOCULATION OF WIL*5TYPE ORGENETICALLY ENGINEERE* HSV 7AOTUS8GENETICALLY ENGINEERE* HSV 7AOTUS8

    A *OSE ESCALATING PHASE ( STU*Y OF AA *OSE ESCALATING PHASE ( STU*Y OF A

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    34/42

    GENETICALLY ENGINEERE* HSV5( IN THEGENETICALLY ENGINEERE* HSV5( IN THETREATMENT OF MALIGNANT GLIOMATREATMENT OF MALIGNANT GLIOMA

    James Car'ert? C+4+ Cichael Cedloc'? C+4+3niversity o0 Alabama at 6eor#eto/n 3niversityIirmin#ham? Iirmin#ham? Cedical $enter? Alabama

    Washin#ton? 4$

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    35/42

    STU*Y OB ECTIVESSTU*Y OB ECTIVES

    PRIMARY OB ECTIVE "o determine the sa0ety and tolerance o0 stereotacticintracerebral inFection o0 escalatin# doses o0 6;@

    SECON*ARY OB ECTIVE "o obtain preliminary in0ormation about the potentialbene1t o0 6;@ in the treatment o0 patients /ithrecurrent mali#nant #liomas (reduction in tumor

    volume)

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    36/42

    STU*Y *ESIGNSTU*Y *ESIGN

    Patients /ith mali#nant #lioma /ho have 0ailedsur#ery!biopsy and radiation%

    &may have had chemotherapy or other treatment

    Cust have pro#ression or recurrence by CRE atleast * /ee's a0ter radiation

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    37/42

    PHASE ( CLINICAL TRIAL OF G53).PHASE ( CLINICAL TRIAL OF G53).

    Patients *ose Vo!&+e7+!8Lo;a!

    x @ @+x @ @+x @ K @+x @ K @+x @ > @+

    x @ > @+ ,x @ > @+ @

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    38/42

    CLINICAL TRIAL SUMMARYCLINICAL TRIAL SUMMARY

    * patients treated over months%

    & no patient developed encephalitis& tumor re#ression 0our patients

    (:uantitative CRE)& one death (secondary to tumor)& next sta#e /ill involve multiloci inoculation

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    39/42

    FUTURE APPROACHES IN HUMANSFUTURE APPROACHES IN HUMANS

    $ombination /ith radiation therapy

    Viruses expressin# cyto'ines or other 0orei#n #enes

    COMBINATION VIRUS AN*COMBINATION VIRUS AN*

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    40/42

    COMBINATION VIRUS ANCOMBINATION VIRUS ANRA*IATION THERAPY RA*IATION THERAPY

    FRACTIONAL TUMOR VOLUME D ()% INITIALFRACTIONAL TUMOR VOLUME D ()% INITIALTUMOR VOLUME U30(MG REGRESSION RATETUMOR VOLUME U30(MG REGRESSION RATE

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    41/42

    TUMOR VOLUME U30(MG REGRESSION RATETUMOR VOLUME U30(MG REGRESSION RATEBASE* ON ENGINEERE* HSV TREATMENTBASE* ON ENGINEERE* HSV TREATMENT

    T eat+ent Vi &s ( 7%8 Vi &s 27%8

    $ontrol @! (@) @! ; (@)

    R" alone ! K ( ) @! ; (@)

    Virus !; ( *) ! ; (K)

    Virus 7R" !; (, ) >! @ (>@)

  • 8/9/2019 Infectia Cu Virus Herpetic a Creierului

    42/42

    CONTRIBUTING INVESTIGATORSCONTRIBUTING INVESTIGATORS

    Uni'e sit" o= A!a#a+aatBi +in >a+Suman Iharana

    6 Nancey 6illespie James Car'ert Jac'ie Par'erRichard Whitley

    Uni'e sit" o=C>i;a oSunil AdvaniIin He

    Iernard Roi manRalph Weichselbaum


Recommended