CHIMERIC PSEUDOTYPED RECOMBINANT RABIES VIRUS
Provided herein are chimeric pseudotyped recombinant RABV particles, wherein the chimeric envelope protein comprises, from N-terminus to C-terminus, a non-RABV envelope protein ectodomain, a non-RABV envelope protein transmembrane domain, and a RABV C-terminal domain. Also provided are methods for their use in delivering a transgene into a target cell.
1 . A pseudotyped recombinant rabies virus (RABV) particle, comprising a chimeric envelope protein and a recombinant RABV genome, wherein:
the chimeric envelope protein comprises, from N-terminus to C-terminus, a non-RABV envelope protein ectodomain, a non-RABV envelope protein transmembrane domain, and a RABV C-terminal domain; and
the recombinant RABV genome does not encode an endogenous envelope protein or fragment thereof and comprises a nucleic acid encoding a therapeutic transgene.
2 . The pseudotyped particle of claim 1 , wherein the chimeric envelope protein retains target receptor binding activity and/or fusion activity compared to a wild-type version of the non-RABV envelope protein.
3 . (canceled)
4 . The pseudotyped particle of claim 1 , wherein the non-RABV envelope protein ectodomain and the non-RABV envelope protein transmembrane domain are from the same envelope protein.
5 . The pseudotyped particle of claim 1 , wherein the RABV C-terminal domain comprises:
(a) an amino acid sequence with at least 90% identity to SEQ ID NO: 390 (RRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGETRL), optionally wherein the RABV C-terminal domain consists of an amino acid sequence SEO ID NO: 390;
(b) an amino acid sequence with at least 90% identity to SEQ ID NO: 391 (RRANRPESKORSFGGTGGNVSVTSOSGKVIPSWESYKSGGEIRL), optionally wherein the RABV C-terminal domain consists of an amino acid sequence SEQ ID NO: 391;
(c) an amino acid sequence with at least 90% identity to SEO ID NO: 392 (KKGGRRNSPTNRPDLPIGLSTTPOPKSKVISSWESYKGTSNV), optionally wherein the RABV C-terminal domain consists of an amino acid sequence SEO ID NO: 392; or
(d) an amino acid sequence with at least 90°/o identity to SEO ID NO: 393 (GRVNRPKSTORNLGGTERKVSVTSOSGKVISSWESYKSGGETRL), optionally wherein the RABV C-terminal domain consists of an amino acid sequence SEO ID NO: 393.
6 - 12 . (canceled)
13 . The pseudotyped particle of claim 1 , wherein the pseudotyped particle comprises one or more properties selected from the group consisting of:
(a) the non-RABV envelope protein ectodomain and/or the non-RABV envelope protein transmembrane domain are not from a lyssavirus;
(b) the non-RABV envelope protein ectodomain comprises an envelope protein ectodomain from a Rhabdoviridae family virus; or
(c) the non-RABV envelope protein transmembrane domain comprises an envelope protein transmembrane domain from a Rhabdoviridae family virus.
14 - 15 . (canceled)
16 . The pseudotyped particle of claim 14 , wherein the Rhabdoviridae family virus comprises an ephemerovirus, a tibrovirus, an almendravirus, a novirhabdovirus, a tupavirus, a nonvirhabdovirus, or a moussa virus (MOUV), optionally wherein the ephemerovirus is bovine ephemeral fever virus (BEFV);
the tibrovirus is an ekpoma virus 1 (EKV1) or an ekpoma virus 2 (EKV2);
the tibrovirus is a Bas-Congo tibrovirus (BASV);
the tibrovirus is a tibrogargan virus (TIBV);
the almendravirus is arboretum virus (ABTV) or balsa virus (BALV);
the nonvirhabdovirus is viral hemorrhagic septicemia virus (VSHV); or
the tupavirus is tupaia Virus (TUPV).
17 . (canceled)
18 . The pseudotyped particle of claim 1 , wherein the non-RABV envelope protein ectodomain and the non-RABV envelope protein transmembrane domain comprises:
(a) a BEFV amino acid sequence comprising at least 90% identity to SEQ ID NO: 395
(MFRVLIITLLARRLHFEKIYNVPVNCGELHPVKAHEIKCPQRLNELSLQAHHNLAKDEH
YNKICRPQLKDDDHLEGFICRKQKWITKCSETWYFSTSIEYQILEVIPEYSGCTDAVKKL
DQGALIPPYYPPAGCFWNTEMNQEIEFYVLIQHKPFLNPYDNLIYDSRFLTPCTINDSKTK
GCPLKDITGTWIPDVRVKEISEHCNSKHWECITVKSFRSELNDTERLWEAPDIGLVHVNK
GCLSTFCGRSGIIFEDGEWWSIENQTESDFQNFKIEKCKGKKPGFRMHTDRTEFEELDIK
AELEHERCLNTISKILNKENINTLDMSYLAPTRPGRDYAYLFEQTSWQEKLCLSLPDSGR
VSKDCSIDWRTSTRGGMVKKNHYGIGSYKRAWCEYRPFIDKNEDGYIDILELNGHNMS
RNHAILETAPAGGSSGTKLNVTLNGMIFVEPTKLYLHTKSIYGGIEEYQKLIKFEVMEYD
NIEENLIKYEEDEKFKPVNLSPHETSQINRTDIVREIQKGGKKVLSAVVGWFTSTAKAVR
WTIWAVGAIVTTYAIYKLYKMVKSN);
(b) a EKV1 amino acid sequence comprising at least 90% identity to SEO ID NO: 397
(MKKTTRRSSSETMILLIHLPVILTTLTKLISGDLINFPFHCTNLENIKYSNLSCPTVWETFK
IKTGDKVERGSMCRPSLHTHDLEEGYLCYKDTWTTTCDESWYFSTEVKYKIIHEEVHDI
DCLDALIEYKVGKLKAPFFPVATCYWASSTTESITFMMIKPHNAPLDPYSNRIVDPIIQAD
SGDNLKIYRTTFPKTRWIREVNTTLEERCNVATWECHDMTLYSGWLTHPSGAFKTSLRT
GLVVDSQIMGHILLRDTCKMDFCGRRGFRFPDGGWWRLTTENEVSLQDFELNDTVVPK
CDDRSRNHVGYTDLDYNPEKIALEQKSLLKTTMCREKLAELGQGKGMSLYDTTYLIPN
APGRYPAYYIYPVGLNKTLETQILKEKTISNPLTAKRKEHMPIMLYMAQCHYTLIEFPNL
DSTGTLRYTSLEDPVGTILESGKNVSLADLGFEDINLDNTTCKGNDSDCFNTTTPKEPLL
DRKFNMTNHTLPWRRYSKRELHHRVTYNGITHSPVGHWVQIPYGASLTANLPEHLIEKH
STHEFDHVTKQSIFERELQNGEISIDDLEQLIGRKTNHTDLPKKVRNWVQNAKESVVGIF
REFGHTIRLGLSIVSFLIGLIISFKVW);
(c) a EKV2 amino acid sequence comprising at least 90% identity to SEQ ID NO: 399
(MQTMKKTHLLAFTIFGQILLASSLVVNLPLRCNGRKDLLVNSLKCPLPSTEVKVDGKV
KVYEGDICRPQINAKDVEAGYLCHKDIYKAICDETWYFSATVKHEIEHAPISDIECIEGLT
ELKLGIVPNPQFPSVDCYWNARTEEKRTYIILTQHDPALDPYSNKIKDNVVDPDCDENLC
KTNFINTKWIRDKNTTEIERCDAKNWDCHPYKIYQGWISKSEMIGWGDPTQSYSYTGLV
LDSHIYGHIPMSKLCHKTFCGKEGYLFPDKSWWQIRSKTPASPLFRELTLNGSRSAFPDC
ETIKTYGYAEVEEDESSEIIRESAEIRHEMCLETLSTLASGYEASFRDLMKFIPQRPGPGKA
YSLNSNGKPSYYNYHWAGHPASSASIQEQDCYYYLVDIPKIQDDGILNITGIGNTDVCGK
LLVNGSSMTLNSLGFKIDHHYDDHIVETGTDVHDEMNIKERMVWIKPDKIHPLLWVGP
NGIVIDHQHKQIHFPVFSRGVDRIPHYWTQKHRVVKYRHATQLKIYKQYLDNPEKSNPY
DFNAWTGRHVNRTEIPVAISNWFSGVKDTVFDKISKIGSWLKWSFYLCFIFVLFKGGLLV
WN);
(d) a BASV amino acid sequence comprising at least 90% identity to SEQ ID NO: 401
(MTRLSHAITKLLLLFCLTAIHAIVINYPTACHTYQEVLYQGLECPEPAISYKLDNNETVA
YGQICRPQLASKDILEGYLCYKDTYISSCEETWYFTSQVKQTIVHEHVSDAECIESLAYY
KSGIVETPMELNVDCYWNAINSIKKSYLIIVYHPVPFDPYTNSIKDAVVKNSEDVNSWIR
DTHYPFTKWIRDFNGTAEEKCDAQHWECFKVNLYKGWIYSPPHTKNTIGSSTQTGLILE
SDIYSHTLIRDLCRFQFCGIHGFVFQDQSWWDLQLNVSLSSLISTEHLSGAPDGHCKKVN
EIGHAELEPNWEKILSVDDYDIRHQLCLDTLASVLGGGFLTARDLLKFAPMRPGLGPAY
FLFNPNKRERAVHVWTAGATTSSILWKSTCKYELIDIPQLNDTGIITYEKLDNIIGKILRN
DVGVSFKDLGFTENELTDDDVSQSQLNSSLGIYHRNTSMKGIPWKRHRASTPKLKMGP
NGILHDLNAKIIHLPQASSSVFKLPPHLYEGHRVVFFNHITKKKIYEDLSKREGNDPYNV
DIGDLIGRHLNRTTIPDQLHDWVSGIKRHIFSVFEQFGSLIKVVVFIIMLVLCIKIINLIYR);
(e) a TIBV amino acid sequence comprising at least 90% identity to SEQ ID NO: 403
(MEAITIEIIIIILTISYPILVAPQLLYNYPENCKKGPKMTLDGLTCPLDFNTENLDSKDNME
AGTMCRPNPLSKDIEDGFLCYKDTWVTTCEETWYFSKTVKNHITHEHITKDECFEALAT
YKLGKHVEPFFPAPSCYWSATNEERATFVNIQPHGVLLDPYSGKIKDPLIDSDNCDNDFC
VTRSHQTHWLRNRKPDIMERCNNETWECHPIKIYYGWVSKKKNQETSTTFNYVQTGLV
IESQYIGHVLMADLCIMTFCNRDGYLFPDGSWWEIKYSLYHAFTKDHTVLNNAHKCGD
RTHGDHLTEFQRDKKVGYEDLEINLEGLEMRQKSRSINMMCLNRLAEIRNTHHINVLD
MSYLTPKHPGRGLAYYFSQDQKNSSKYHVKVLDCDYKLIHIHDADIKGFVNITKYPEPN
VTILGLKDNLTFADLGISRCQDLTPLNGSRNISCEESSGPLHSDDSRLSNGKRFWTRHSFQ
GANFHEHPGVRIGVNGITYDIRKQILRFPSTSNLLWDLPSYYSTKHRVHFFQHPTKHEIRK
NFTGSDSRDIDVLDDLINRHINRTDFPTRIRNWIGNIEDKVEHFFSNVGGTIKTIISLVLFVI
GTLISIKVWKKCK);
(f) an ABTV amino acid sequence comprising at least 90% identity to SEO ID NO: 405
(MIAHKLILPLVILTSFQRIKREDITCPVYNHKNVNVSSQSLLQFDMRQVSENSGEEIINHN
PLVTGYLCRKLSYETSCYANLFTSNTVEYKLKILPITKKECATGSNSQVKSFPTPICNWS
MFGSNTVKETKQYIEYEQRSYKLDMVSGKLKHVEEIFDKCYEEYCVLKDNSGYWIRDD
QDEKKYCPKLEDQKIPAKLKVIDQFEYLEVAQHIYDMQELCALEVCGNMLIHIPDIGNFI
GDDRFMKKLKKCKSLPSLRNAIENNSEDITGNEKCLDFRLKMLGNPDKSIKYHDIRNLH
PRSPGINRVYRLGENNTLESAIAYYGSTGLDKISKKLNYWVNCTEDKVCSYNGYMGKD
KLHLRSKLDSETYQDIFEVDDELIVYQPTRNISESFYKDVIHYELLDKMTQNFSIFNSNYY
SKIIYALLIILAVFFIYKIMKLLTLRC);
(g) an BALV amino acid sequence comprising at least 90% identity to SEO ID NO: 407
(MFFTILPTLLLGNWTLVNITDITCPHYKDYTIHPEAINHKLSLYEVTDEDYNEYNNVLFG
RDCSKLTLSTKCKAHLMASNEIEYEEIYESPDITDCNSLKMDNMIKYPESNCRWNLFDN
GYISNNETTIKINDKSFLLDVHTGLIVNQDKIFNHCDEHMCEYKNNRGFWLRSKDINTEK
ELCTHLKNTTHINKQEGYLSVYQNNKFLYIENNPVHYDDMCTIKRCNNLILTIKNFKKY
VIKSSGLFQECKTDNIHYLNKEESFNEVEDHILCANKLVKVIKEKKLNYYDLKYFHPTRI
GLHNIYRLNEDKKLEKNIAYYSKVDSDKDEVKVKSVACGTKVNCLYNGKHKINSEKEF
NVDIKEYKIYKDEVEKGFIIEDSMYIPYEKTEIEFERNAITFDFDEIYKFGMGLLIIALILLIL
VCVVTKC)
(h) an VSHV amino acid sequence comprising at least 90% identity to SEO ID NO: 409
(MAHLCTQQARPMEWNTFFLVILIIIIKSTTPQITQRPPVENISTYHADWDTPLYTHPSNCR
DDSFVPIRPAQLRCPHEFEDINKGLVSVPTKIIHLPLSVTSVSAVASGHYLHRVTYRVTCS
TSFFGGQTIEKTILEAKLSRQEATDEASKDHEYPFFPEPSCIWMKNNVHKDITHYYKTPK
TVSVDLYSRKFLNPDFIEGVCTTSPCQTHWQGVYWVGATPKAHCPTSETLEGHLFTRTH
DHRVVKAIVAGHHPWGLTMACTVTFCGAEWIKTDLGDLIQVTGPGGTGKLTPKKCVN
ADVQMRGATDDFSYLNHLITNMAQRTECLDAHSDITASGKISSFLLSKFRPSHPGPGKA
HYLLNGQIMRGDCDYEAVVSINYNSAQYKTVNNTWKSWKRVDNNTDGYDGMIFGDK
LIIPDIEKYQSVYDSGMLVQRNLVEVPHLSIVFVSNTSDLSTNHIHTNLIPSDWSFHWSIW
PSLSGMGVVGGAFLLLVLCCCCK);
(i) an TUPV amino acid sequence comprising at least 90% identity to SEQ ID NO: 411
(MAPQTISLLWAMVCVSVYTRANRVVAPIHEPQNWKPATVDDFTCRTGFNLDEDSKFIK
TKALVLKRVGQAKVKGYLCMKNRWTTTCETNWLYSKSVSHHITHVAVSAEECYNKIR
DDASGNLKIESYPNPQCAWSSTVSREEDFIHISTSDVGYDMYTDTVLSPSFPGGTCKLKT
CCKTIYPNIVWVPETPAQTQVRDALFDETMVTVTVEAKKVVKDSWVTGATITPSVMEG
SCKKTLGSKSGILLPNGQWESIVETGQITIQPKGSVEEKETWVNLINDLNLSDCAETQEA
KVPTAEFTVYKTESMVFNILNYHLCLETVAKARSGKNLTRLDLARLAPEIPGVAHVYQL
TSDGVRVGSTRYEIIAWKPTMGLDKTLGLTIVPSGNRNSETIKWIEWTRTDDGLLNGPN
GIFIADGKEIVHPNLKMVSFELETYLISEHSTQLVPHPVIHSISDEIYPENYTIGGKNSYIKI
HTPTAYFWSGIHWIEGAVQKLFIVVVATALIGLFILVVWLCCGC);
or
(j) an MOUV amino acid sequence comprising at least 90% identity to SEQ ID NO: 413
(MRTLVIWFLINVTMAFAKPPGSASLSLGLYWVPRIDNNTWKSVHTTNLVCPSFVGSVLP
EMEESFEIDIQVPKHSQTTSHQGGYLCYGESFSVVCEEGFWGGQKVTEHTFTHLVSSEEC
LKAIEDKKSGEYRPPHTPVSECGWMQTNTKTLRFVTLEEHPVLFDPYTVNFVDGLFEKT
LCNQRICPTVHANTIWIGDNEPKKDCPPTENEKAVLYVEKQNVVPVVWVKLTGGTVYK
LDRACTMTYCDIDGVRMEDGHWFAGVNLTQYVRRDCDKGMDITFDTLASLSLLTKIEL
EHVQDRMECLDAVQDLRAGGKVTYAKLSKLQPKRGGLFHVYRINKGTLEYTMGRYEG
LTSLITNIPEVIGKNQKDEKVQLHHVPSGDNSTLSSYNGVHMFLNGTVIIPEMELYKLRY
SETLLYEHLLGKMKHPSAKQRERMGLTPDDDKRTTNKSLNIGEWFSSFWSHLVGKIVSI
LGTALAIFLILYICWTCLK
19 . The pseudotyped particle of claim 1 , wherein the chimeric envelope protein comprises an amino acid sequence comprising at least 90% identity to;
(a) SEQ ID NO: 396
(MFRVLIITLLARRLHFEKIYNVPVNCGELHPVKAHEIKCPQRLNELSLQAHHNLAKDEH
YNKICRPQLKDDDHLEGFICRKQKWITKCSETWYFSTSIEYQILEVIPEYSGCTDAVKKL
DQGALIPPYYPPAGCFWNTEMNQEIEFYVLIQHKPFLNPYDNLIYDSRFLTPCTINDSKTK
GCPLKDITGTWIPDVRVKEISEHCNSKHWECITVKSFRSELNDTERLWEAPDIGLVHVNK
GCLSTFCGRSGIIFEDGEWWSIENQTESDFQNFKIEKCKGKKPGFRMHTDRTEFEELDIK
AELEHERCLNTISKILNKENINTLDMSYLAPTRPGRDYAYLFEQTSWQEKLCLSLPDSGR
VSKDCSIDWRTSTRGGMVKKNHYGIGSYKRAWCEYRPFIDKNEDGYIDILELNGHNMS
RNHAILETAPAGGSSGTKLNVTLNGMIFVEPTKLYLHTKSIYGGIEEYQKLIKFEVMEYD
NIEENLIKYEEDEKFKPVNLSPHETSQINRTDIVREIQKGGKKVLSAVVGWFTSTAKAVR
WTIWAVGAIVTTYAIYKLYKMVKSNRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWE
SHKSGGETRL);
(b) SEQ ID NO: 398
(MKKTTRRSSSETMILLIHLPVILTTLTKLISGDLINFPFHCTNLENIKYSNLSCPTVWETFK
IKTGDKVERGSMCRPSLHTHDLEEGYLCYKDTWTTTCDESWYFSTEVKYKIIHEEVHDI
DCLDALIEYKVGKLKAPFFPVATCYWASSTTESITFMMIKPHNAPLDPYSNRIVDPIIQAD
SGDNLKIYRTTFPKTRWIREVNTTLEERCNVATWECHDMTLYSGWLTHPSGAFKTSLRT
GLVVDSQIMGHILLRDTCKMDFCGRRGFRFPDGGWWRLTTENEVSLQDFELNDTVVPK
CDDRSRNHVGYTDLDYNPEKIALEQKSLLKTTMCREKLAELGQGKGMSLYDTTYLIPN
APGRYPAYYIYPVGLNKTLETQILKEKTISNPLTAKRKEHMPIMLYMAQCHYTLIEFPNL
DSTGTLRYTSLEDPVGTILESGKNVSLADLGFEDINLDNTTCKGNDSDCENTTTPKEPLL
DRKFNMTNHTLPWRRYSKRELHHRVTYNGITHSPVGHWVQIPYGASLTANLPEHLIEKH
STHFFDHVTKQSIFERELQNGEISIDDLEQLIGRKTNHTDLPKKVRNWVQNAKESVVGIF
REFGHTIRLGLSIVSFLIGLIISFKVWRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWES
HKSGGETRL);
(c) SEO ID NO: 400
(MQTMKKTHLLAFTIFGQILLASSLVVNLPLRQNGRKDLLVNSLKCPLPSTEVKVDGKV
KVYEGDICRPQINAKDVEAGYLCHKDIYKAICDETWYFSATVKHEIEHAPISDIECIEGLT
ELKLGIVPNPQFPSVDCYWNARTEEKRTYIILTQHDPALDPYSNKIKDNVVDPDCDFNLC
KTNFINTKWIRDKNTTEIERCDAKNWDCHPYKIYQGWISKSEMIGWGDPTQSYSYTGLV
LDSHIYGHIPMSKLCHKTFCGKEGYLFPDKSWWQIRSKTPASPLFRELTLNGSRSAFPDC
ETIKTYGYAEVEEDESSEIIRESAEIRHEMCLETLSTLASGYEASFRDLMKFIPQRPGPGKA
YSLNSNGKPSYYNYHWAGHPASSASIQEQDCYYYLVDIPKIQDDGILNITGIGNTDVCGK
LLVNGSSMTLNSLGFKIDHHYDDHIVETGTDVHDEMNIKERMVWIKPDKIHPLLWVGP
NGIVIDHQHKQIHFPVFSRGVDRIPHYWTQKHRVVKYRHATQLKIYKQYLDNPEKSNPY
DENAWTGRHVNRTEIPVAISNWFSGVKDTVEDKISKIGSWLKWSFYLCFIFVLFKGGLLV
WNRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGETRL);
(d) SEO ID NO. 402
(MTRLSHAITKLLLLFCLTAIHAIVINYPTACHTYQEVLYQGLECPEPAISYKLDNNETVA
YGQICRPQLASKDILEGYLCYKDTYISSCEETWYFTSQVKQTIVHEHVSDAECIESLAYY
KSGIVETPMFLNVDCYWNAINSIKKSYLIIVYHPVPFDPYTNSIKDAVVKNSEDVNSWIR
DTHYPFTKWIRDENGTAEEKCDAQHWECFKVNLYKGWIYSPPHTKNTIGSSTQTGLILE
SDIYSHTLIRDLCRFQFCGIHGFVFQDQSWWDLQLNVSLSSLISTEHLSGAPDGHCKKVN
EIGHAELEPNWEKILSVDDYDIRHQLCLDTLASVLGGGFLTARDLLKFAPMRPGLGPAY
FLFNPNKRERAVHVWTAGATTSSILWKSTCKYELIDIPQLNDTGIITYEKLDNIIGKILRN
DVGVSFKDLGFTENELTDDDVSQSQLNSSLGIYHRNTSMKGIPWKRHRASTPKLKMGP
NGILHDLNAKIIHLPQASSSVFKLPPHLYEGHRVVFFNHITKKKIYEDLSKREGNDPYNV
DIGDLIGRHLNRTTIPDQLHDWVSGIKRHIFSVFEQFGSLIKVVVFIIMLVLCIKIINLIYRR
RVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGETRL);
(e) SEO ID NO: 404
(MEAITIEIIIIILTISYPILVAPQLLYNYPFNCKKGPKMTLDGLTCPLDENTENLDSKDNME
AGTMCRPNPLSKDIEDGFLCYKDTWVTTCEETWYFSKTVKNHIIHEHITKDECFEALAT
YKLGKHVEPFFPAPSCYWSATNEERATFVNIQPHGVLLDPYSGKIKDPLIDSDNCDNDFC
VTRSHQTHWLRNRKPDIMERCNNETWECHPIKIYYGWVSKKKNQETSTTFNYVQTGLV
IESQYIGHVLMADLCIMTFCNRDGYLFPDGSWWEIKYSLYHAFTKDHTVLNNAHKCGD
RTHGDHLTEFQRDKKVGYEDLEINLEGLEMRQKSRSINMMCLNRLAEIRNTHHINVLD
MSYLTPKHPGRGLAYYFSQDQKNSSKYHVKVLDCDYKLIHIHDADIKGFVNITKYPEPN
VTILGLKDNLTFADLGISRCQDLTPLNGSRNISCEESSGPLHSDDSRLSNGKRFWTRHSFQ
GANFHEHPGVRIGVNGITYDIRKQILRFPSTSNLLWDLPSYYSTKHRVHFFQHPTKHEIRK
NFTGSDSRDIDVLDDLINRHINRTDFPTRIRNWIGNIEDKVEHFFSNVGGTIKTIISLVLFVI
GTLISIKVWKKCKRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGETRL);
(f) SEQ ID NO: 406
(MIAHKLILPLVILTSFQRIKREDITCPVYNHKNVNVSSQSLLQFDMRQVSENSGEEIINHN
PLVTGYLCRKLSYETSCYANLFTSNTVEYKLKILPITKKECATGSNSQVKSFPTPICNWS
MFGSNTVKETKQYIEYEQRSYKLDMVSGKLKHVEEIFDKCYEEYCVLKDNSGYWIRDD
QDEKKYCPKLEDQKIPAKLKVIDQFEYLEVAQHIYDMQELCALEVCGNMLIHIPDIGNFI
GDDRFMKKLKKCKSLPSLRNAIENNSEDITGNEKCLDFRLKMLGNPDKSIKYHDIRNLH
PRSPGINRVYRLGENNTLESAIAYYGSTGLDKISKKLNYWVNCTEDKVCSYNGYMGKD
KLHLRSKLDSETYQDIFEVDDELIVYQPTRNISESFYKDVIHYELLDKMTQNFSIFNSNYY
SKIIYALLIILAVFFIYKIMKLLTLRCRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWES
HKSGGETRL);
(g) an amino acid sequence comprising at least 90% identity to SEQ ID NO: 408
(MFFTILPTLLLGNWTLVNITDITCPHYKDYTIHPEAINHKLSLYEVTDEDYNEYNNVLFG
RDCSKLTLSTKCKAHLMASNEIEYEEIYESPDITDCNSLKMDNMIKYPESNCRWNLFDN
GYISNNETTIKINDKSFLLDVHTGLIVNQDKIFNHCDEHMCEYKNNRGFWLRSKDINTEK
ELCTHLKNTTHINKQEGYLSVYQNNKFLYIENNPVHYDDMCTIKRCNNLILTIKNFKKY
VIKSSGLFQECKTDNIHYLNKEESFNEVEDHILCANKLVKVIKEKKLNYYDLKYFHPTRI
GLHNIYRLNEDKKLEKNIAYYSKVDSDKDEVKVKSVACGTKVNCLYNGKHKINSEKEF
NVDIKEYKIYKDEVEKGFIIEDSMYIPYEKTEIEFERNAITFDFDEIYKFGMGLLIIALILLIL
VCVVTKCRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGETRL);
(h) SEQ ID NO: 410
(MAHLCTQQARPMEWNTFFLVILIIIIKSTTPQITQRPPVENISTYHADWDTPLYTHPSNCR
DDSFVPIRPAQLRCPHEFEDINKGLVSVPTKIIHLPLSVTSVSAVASGHYLHRVTYRVTCS
TSFFGGQTIEKTILEAKLSRQEATDEASKDHEYPFFPEPSCIWMKNNVHKDITHYYKTPK
TVSVDLYSRKFLNPDFIEGVCTTSPCQTHWQGVYWVGATPKAHCPTSETLEGHLFTRTH
DHRVVKAIVAGHHPWGLIMACTVTFCGAEWIKTDLGDLIQVTGPGGTGKLTPKKCVN
ADVQMRGATDDFSYLNHLITNMAQRTECLDAHSDITASGKISSFLLSKFRPSHPGPGKA
HYLLNGQIMRGDCDYEAVVSINYNSAQYKTVNNTWKSWKRVDNNTDGYDGMIFGDK
LIIPDIEKYQSVYDSGMLVQRNLVEVPHLSIVFVSNTSDLSTNHIHTNLIPSDWSFHWSIW
PSLSGMGVVGGAFLLLVLCCCCKRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESH
KSGGETRL);
(i) SEO ID NO: 412
(MAPQTISLLWAMVCVSVYTRANRVVAPIHEPQNWKPATVDDFTCRTGFNLDFDSKFIK
TKALVLKRVGQAKVKGYLCMKNRWTTTCETNWLYSKSVSHHITHVAVSAEECYNKIR
DDASGNLKIESYPNPQCAWSSTVSREEDFIHISTSDVGYDMYTDTVLSPSFPGGTCKLKT
CCKTIYPNIVWVPETPAQTQVRDALFDETMVTVTVEAKKVVKDSWVTGATITPSVMEG
SCKKTLGSKSGILLPNGQWFSIVETGQITIQPKGSVEEKETWVNLINDLNLSDCAETQEA
KVPTAEFTVYKTESMVFNILNYHLCLETVAKARSGKNLTRLDLARLAPEIPGVAHVYQL
TSDGVRVGSTRYEIIAWKPTMGLDKTLGLTIVPSGNRNSETIKWIEWTRTDDGLLNGPN
GIFIADGKEIVHPNLKMVSFELETYLISEHSTQLVPHPVIHSISDEIYPENYTIGGKNSYIKI
HTPTAYFWSGIHWIEGAVQKLFIVVVATALIGLFILVVWLCCGCRRVNRSEPTQHNLRG
TGREVSVTPQSGKIISSWESHKSGGETRL);
(j) SEO ID NO: 414
(MRTLVIWFLINVTMAFAKPPGSASLSLGLYWVPRIDNNTWKSVHTTNLVCPSFVGSVLP
EMEESFEIDIQVPKHSQTTSHQGGYLCYGFSFSVVCEEGFWGGQKVTEHTFTHLVSSEEC
LKAIEDKKSGEYRPPHTPVSECGWMQTNTKTLRFVTLEEHPVLFDPYTVNFVDGLFEKT
LCNQRICPTVHANTIWIGDNEPKKDCPPTENEKAVLYVEKQNVVPVVWVKLTGGTVYK
LDRACTMTYCDIDGVRMEDGHWFAGVNLTQYVRRDCDKGMDITFDTLASLSLLTKIEL
EHVQDRMECLDAVQDLRAGGKVTYAKLSKLQPKRGGLFHVYRINKGTLEYTMGRYEG
LTSLITNIPFVIGKNQKDEKVQLHHVPSGDNSTLSSYNGVHMFLNGTVIIPEMELYKLRY
SETLLYEHLLGKMKHPSAKQRERMGLTPDDDKRTINKSLNIGEWESSFWSHLVGKIVSI
LGTALAIFLILYICWTCLKRRVNRSEPTQHNLRGTGREVSVTPQSGKIISSWESHKSGGET
RL).
20 - 43 . (canceled)
45 . The pseudotyped particle of claim 1 , wherein the nucleic acid encoding the therapeutic transgene is greater than: about 300 bp, about 400 bp, about 500 bp, about 600 bp, about 700 bp, about 800 bp, about 900 bp, about 1,000 bp, about 1,100 bp, about 1,200 bp, about 1,300 bp, about 1,400 bp, about 1,500 bp, about 1,600 bp, about 1,700 bp, about 1,800 bp, about 1,900 bp, about 2,000 bp, about 2,100 bp, about 2,200 bp, about 2,300 bp, about 2,400 bp, about 2,500 bp, about 2,600 bp, about 2,700 bp, about 2,800 bp, about 2,900 bp, or about 3,000 bp, optionally wherein the therapeutic transgene is greater than about 300 bp, about 650 bp, about 1.000 bp, about 3,000 bp, about 4,500 bp, about 8.500 bp, or about 10,000 bp.
46 - 52 . (canceled)
53 . The pseudotyped particle of claim 1 , wherein the therapeutic transgene comprises a nucleic acid editing system or a component thereof, optionally wherein the nucleic acid editing system or component thereof is selected from the group consisting of: a Clustered Regulatory Interspaced Short Palindromic Repeat (CRISPR) system, a zinc finger protein (ZF), a meganuclease, and a Transcription Activator-Like Effector-based protein (TALE).
54 - 55 . (canceled)
56 . The pseudotyped particle of claim 53 , wherein the CRISPR-system comprises a nucleobase editor comprising a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain, optionally wherein
the nucleobase editing domain is an adenosine deaminase, cytidine deaminase, cytosine deaminase, or a functional variant thereof;
the adenosine deaminase is selected from the group consisting of: ABE 0.1, ABE 0.2, ABE 1.1, ABE 1.2, ABE2.1, ABE2.2, ABE2.3, ABE2.4, ABE2.5, ABE2.6, ABE2.7, ABE2.8, ABE2.9, ABE2.10, ABE2.11, ABE2.12, ABE3.1, ABE3.2, ABE3.3, ABE3.4, ABE3.5, ABE3.6, ABE3.7, ABE3.8, ABE4.1, ABE4.2, ABE4.3 ABE5.1 ABE5.2, ABE5.3, ABE5.4 ABE5.5 ABE5.6, ABE5.7, ABE5.8 ABE5.9 ABE5.10, ABE5.11 ABE5.12, ABE5.13 ABE5.14, ABE6.1, ABE6.2, ABE6.3, ABE6.4, ABE6.5, ABE6.6, ABE7.1, ABE7.2, ABE7.3, ABE7.4, ABE7.5, ABE7.6, ABE7.7, ABE7.8, ABE7.9, ABE7.10, ABE8.1-m, ABE8.2-m, ABE8.3-m, ABE8.4-m, ABE8.5-m, ABE8.6-m, ABE8.7-m, ABE8.8-m, ABE8.9-m, ABE8.10-m, ABE8.11-m, ABE8.12-m, ABE8 13-m, ABE8.14-m, ABE8.15-m, ABE8.16-m, ABE8.17-m, ABE8.18-m, ABE8.19-m, ABE8.20-m, ABE8.21-m, ABE8.22-m, ABE8.23-m, ABE8.24-m, ABE8.1-d, ABE8.2-d, ABE8.3-d, ABE8.4-d, ABE8.5-d, ABE8.6-d, ABE8.7-d, ABE8.8-d, ABE8.9-d, ABE8.10-d, ABE8.11-d, ABE8.12-d, ABE8.13-d, ABE8.14-d, ABE8.15-d, ABE8.16-d, ABE8.17-d, ABE8.18-d, ABE8.19-d, ABE8.20-d, ABE8.21-d, ABE8.22-d, ABE8.23-d, ABE8.24-d, ABE8a-m, ABE8b-m, ABE8c-m, ABE8d-m, ABE8e-m, ABE8a-d, ABE8b-d, ABE8c-d, ABE8d-d, ABE8e-d, ABE9.1, ABE9.2, ABE9.3, ABE9.4, ABE9.5, ABE9.6, ABE9.7, ABE9.8, ABE9.9, ABE9.10, ABE9.11, ABE9.12, ABE9.13, ABE9.14, ABE9.15, ABE9.16, ABE9.17, ABE9.18, ABE9.19, ABE9.2, ABE9.21 ABE9.22 ABE9.23, ABE9.24, ABE9.25, ABE9.26, ABE9.27, ABE9.28, ABE9.29, ABE9.30, ABE9.31, ABE9.32, ABE9.33, ABE9.34, ABE9.35, ABE9.36, ABE9.37, ABE9.38, ABE9.39 ABE9.40 ABE9.41, ABE9.42, ABE9.43 ABE9.44 ABE9.45, ABE9.46, ABE9.47, ABE9.48, ABE9.49, ABE9.50, ABE9.51, ABE9.52, ABE9.53, ABE9.54, ABE9.55, ABE9.56, ABE9.57, and ABE9.58;
the polynucleotide programmable nucleotide binding domain is a Cas9 polypeptide, a Cas12 polypeptide, or a functional variant thereof; or
the CRISPR-system further comprises a guide RNA (RNA) or a nucleic acid sequence encoding a gRNA.
57 - 62 . (canceled)
63 . The pseudotyped particle of claim 1 , wherein the therapeutic transgene comprises a therapeutic polypeptide and/or a therapeutic nucleic acid optionally wherein the therapeutic transgene is operably linked to a transcriptional regulatory element.
64 . (canceled)
65 . The pseudotyped particle of claim 63 , wherein the transcriptional regulatory element comprises a transcription initiation signal, optionally wherein
the transcription initiation signal is exogenous or endogenous to the rabies virus; and/or
the therapeutic transgene is operably linked to a transcription termination polyadenylation signal.
66 - 68 . (canceled)
69 . The pseudotyped particle of claim 1 , wherein the recombinant RABV genome lacks;
a G gene encoding for a envelope protein or a functional variant thereof, and/or the genome lacks an L gene encoding for a polymerase or a functional variant thereof;
a G gene encoding for a envelope protein or a functional variant thereof;
a G gene encoding for a envelope protein or a functional variant thereof, and wherein the genome lacks an L gene encoding for a polymerase or a functional variant thereof;
a G gene encoding for a envelope protein or a functional variant thereof, and wherein the genome lacks an L gene encoding for a polymerase or a functional variant thereof; and/or
an N gene encoding for a nucleoprotein or a functional variant thereof, a P gene encoding for a phosphoprotein or a functional variant thereof, and/or an M gene encoding for a matrix protein or a functional variant thereof.
70 - 71 . (canceled)
72 . The pseudotyped particle of claim 1 , wherein the recombinant RABV genome comprises:
an N gene encoding for a nucleoprotein or a functional variant thereof;
a P gene encoding for a phosphoprotein or a functional variant thereof; and
an M gene encoding for a matrix protein or a functional variant thereof.
73 . (canceled)
74 . The pseudotyped particle of claim 1 , wherein the recombinant RABV particle is capable of transducing a human cell, wherein the human cell expresses the therapeutic transgene.
75 . The pseudotyped particle of claim 1 , wherein the recombinant RABV genome does not encode an envelope protein or fragment thereof.
76 . A pharmaceutical composition comprising the pseudotyped particle of claim 1 .
77 . A method for expressing a therapeutic transgene in a target cell, comprising transducing a target cell with the pseudotyped particle of claim 1 , optionally wherein the target cell is a human cell and/or the target cell is in a human.
78 .- 79 . (canceled)
80 . A method for delivering a therapeutic transgene to a subject, comprising administering to the subject the pseudotyped particle of claim 1 .