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US 20170020926A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0020926 A1 Mata-Fink et al. (43) Pub. Date: Jan. 26, 2017 (54) METHODS AND COMPOSITIONS FOR 62/006,825, filed on Jun. 2, 2014, provisional appli MMUNOMODULATION cation No. 62/006,829, filed on Jun. 2, 2014, provi sional application No. 62/006,832, filed on Jun. 2, (71) Applicant: RUBIUS THERAPEUTICS, INC., 2014, provisional application No. 61/991.319, filed Cambridge, MA (US) on May 9, 2014, provisional application No. 61/973, 764, filed on Apr. 1, 2014, provisional application No. (72) Inventors: Jordi Mata-Fink, Somerville, MA 61/973,763, filed on Apr. 1, 2014. (US); John Round, Cambridge, MA (US); Noubar B. Afeyan, Lexington, (30) Foreign Application Priority Data MA (US); Avak Kahvejian, Arlington, MA (US) Nov. 12, 2014 (US) ................. PCT/US2O14/0653O4 (21) Appl. No.: 15/301,046 Publication Classification (22) PCT Fed: Mar. 13, 2015 (51) Int. Cl. A6II 35/28 (2006.01) (86) PCT No.: PCT/US2O15/02O614 CI2N 5/078 (2006.01) (52) U.S. Cl. S 371 (c)(1), CPC ............. A61K 35/28 (2013.01); C12N5/0641 (2) Date: Sep. 30, 2016 (2013.01): CI2N 5/0644 (2013.01); A61 K Related U.S. Application Data 2035/122 (2013.01) (60) Provisional application No. 62/059,100, filed on Oct. (57) ABSTRACT 2, 2014, provisional application No. 62/025,367, filed on Jul. 16, 2014, provisional application No. 62/006, Provided are cells containing exogenous antigen and uses 828, filed on Jun. 2, 2014, provisional application No. thereof. Patent Application Publication Jan. 26, 2017. Sheet 1 of 27 US 2017/0020926 A1 ?---- 0!10 x-exexerxxxxxxxxx ? &~~~~~~~~);% |*g************ ?zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz) |61 seuuosod?TON unOO 961 unOO Patent Application Publication Jan. 26, 2017. Sheet 2 of 27 US 2017/0020926 A1 Expand Diff 1 Diff 2 Diff 3 Diff 3 Diff 3 Diff 3 D6 D5 D4 D2 D4 D6 D8 Fig 2 Patent Application Publication Jan. 26, 2017. Sheet 3 of 27 US 2017/0020926 A1 - Transgene + Transgene as R17 R18 s 1 O O vessexy syssessiyssessssssexesex Fig" 3A 100-corroriscorer100 to 1102103 104 105106 1OV0235 10 10%-10 1 0 1 0 10 - Transgene + Transgene Waasaasa-Ya- w88ws & woxx's systSSYYYYYYYYYYYYYYYYYYYYYYYYY. S R1 s R11 s s R1 SX S 8 3. s S. S 103 s S S 11 S s R17 Ss i O S 00.100101102103 Nasses &Ssssssss-xxx-xx-xx-104 105 106 100101102103*S-isssssss'. $xxxss- 104systesssss 10510Ks--sixx-xxs6 S3 + Transgene 1 O 57 O 2 Patent Application Publication Jan. 26, 2017. Sheet 4 of 27 US 2017/0020926 A1 s. Ya-Ya-YYYYYY---W. 2 y s Ww ---------- ''' ---. 2 -----...-- 2 % 2 . % 2 2 22 2 % W.% 22 2. 2. % --- % 2. * 2. 2 % 3 % 3 2. % - . - Patent Application Publication Jan. 26, 2017. Sheet 5 of 27 US 2017/0020926 A1 % % % ... ». 2. '''% . % %%2-2.% + Transgene R3 iR4 s R5 a 100 100 isxxx 100101102103 104 105106 100101102103 104 105106 Patent Application Publication Jan. 26, 2017. Sheet 6 of 27 US 2017/0020926 A1 - Transgene + Transgene saxoxx-xx-xx-xx-xx-xx-xxxxess 106 R2 1O 5. 104 102 101 R4 100-r - 100 ser 100101102103 10? 105106 100 101 102103 104 105 106 - Transgene + Transgene - Transgene "038 kx-r-sciss-s-s-s-re:cis-ressw-ry95.4 series"x:1.81 1062.5irport sess rerorécyst-error-sex-ress--0.0817 Fig 3L 102 10 106 102 10 106 Patent Application Publication Jan. 26, 2017. Sheet 7 of 27 US 2017/0020926 A1 + Transgene 2 % % %s% - + Transgene 62 Anti-HA 38 28 Patent Application Publication Jan. 26, 2017. Sheet 8 of 27 US 2017/0020926 A1 w Transgene Transgene 1OO . s 106 105 105. 104 104. 10- -10° 102 ... : : 102. 101 - * | 101. Fig 3T to 1OW 10 10 10 1 0 10 - Transgene + Transgene s 6 S. 1 s R 1 O 5 s& *s R17 -ressesssssss-exsessssss- assassessesssexes assissists&E 104 105 10 3 104 105 106 s Ss s 10.1 s 88.8 3xers"reyss-re-six;xxxix-sex-rvystroysey-s-s 102 10 106 Patent Application Publication Jan. 26, 2017. Sheet 9 of 27 US 2017/0020926 A1 - Transgene + Transgene systwyxypreservers104 106 105. 104. S. 103 'sS. 10983 0.0622 101 $ss-exissyrisonerswys76.9 & vessess 10 10 10 102 104 10 - Transgene + Transgene 1071.63 0.0497 1079.88xxxxxxxxxxxxx xxxxxxxxxxxxx 0.497 y 0.0622 101894 S.issisteresy:*siysk-sessrssegressessex: s&xxx xxxx ass sysexes: is-ories-s-s-s-s-s-s-s-ressex 102 10 10 6 102 10 10 6 Patent Application Publication Jan. 26, 2017. Sheet 10 of 27 US 2017/0020926 A1 c Transgene Transgene 0.45 1 04 105 o6 - Transgene Patent Application Publication Jan. 26, 2017. Sheet 11 of 27 US 2017/0020926 A1 v Transgene Transgene & a va 6 6 2 1 O R2 1 1 1 1 O 3. 1 O 2 1 O 1 s 1 O i R4 R5 O " ... R5 100s100101102103 10'105106 1O 1001011021030405106* Yixery series SS - Transgene + Transgene - opo S R2 S R3 S S s s s as s x 100 ---- anol R -- 100101102 2103 104 105 106 R3 s 100 acrosses area Fig 3AE 0 1 2 3 4 5 oô Patent Application Publication Jan. 26, 2017. Sheet 12 of 27 US 2017/0020926 A1 - Transgene + Transgene 1 O O Neyeseiosyo-eR4 NeR5 1 O0 iyessR4 - - - - exemyeR5 Fig 3AF 10010110210° 10'105106 100101102103 104 105106 - Transgene +-Transgene 89systery's Nysseyreysseysis 102 104 106 - Transgene 0.0256 s v. .. 3.8 *res-s-s-s-six-x-xx-s-s-s-s-s-sers:-102 104 106 Patent Application Publication Jan. 26, 2017. Sheet 13 of 27 US 2017/0020926 A1 - Transgene +Transgene s 1 O 6 4 1 4 1 O 2 O S. 14.9 0 irregri.104 10510 - s & OO 46 &s s s. & O 2 s O s Fig 3AJ -s-s-s-s-s-rrrrrrrrrrrrrrr-e-r-sers0 10 10° 10 & Patent Application Publication Jan. 26, 2017. Sheet 14 of 27 US 2017/0020926 A1 - Transgene + Transgene 7 R G F P s 243 1 $$$$...isS3. Fig 3AM 10010110210°s 10'10° 106 +Transgene 69. 8 1 O 6 1 O 4 r S 0.0703 8 s | s swiss-sixstows-sex102 104 106 years-w sewers10 x: s rare Patent Application Publication Jan. 26, 2017. Sheet 15 of 27 US 2017/0020926 A1 Transgene * Transgene 1070.361 106. 105. Ep 104 103. 102. 101 99.1 resswynwyswyswyswyx Sis sessessessexei Fig 3AQ 102 104 106 102 104 106 - Transgene Transgene XX 0.246 107,0.0318 1 O 6.: s ' 0.318 : s 75.7 series-crossero4" "6 Šs s^ess s&sseswaxswaisy's104 106 - Transgene +Transgene 0.246 1070.0471 18.1 O 2. 10199.1 0.318101.i issessive8 systerseesi3. s 2.28 Fig 3AS 102 04 106 Patent Application Publication Jan. 26, 2017. Sheet 16 of 27 US 2017/0020926 A1 % 2 2. % 3 W. Patent Application Publication Jan. 26, 2017. Sheet 17 of 27 US 2017/0020926 A1 &&******** Oy61 d=15) unoC) Patent Application Publication Jan. 26, 2017. Sheet 18 of 27 US 2017/0020926 A1 gC Transduced D to N CNS sS OOS 53 . S - I - E E E 52 E E SE SE SE SE 51 ... D C C C C ?h - 50 -------------. d 3 49 or 48 a v- a v. W. W. v- a v- a - a - m a a V a m - m - a v- a v- a O 47 ... 46 - 45 . d-tubulin 44 ................ B-actin - Transgene N+ Transgene FiOI9 5A Fig 5B Transduced O-tubulin - Transgene 3-ac-actin R+ Transgene Fig 5C Fig 5D Patent Application Publication Jan. 26, 2017. Sheet 19 of 27 US 2017/0020926 A1 IC SBSA + IgG s s s IC binding Fig 6A 25000 Ceis only i20000 OBSA-IgG e siC 15000 10000 5000 Patent Application Publication Jan. 26, 2017. Sheet 20 of 27 US 2017/0020926 A1 g/61 CI/61 8 Patent Application Publication Jan. 26, 2017. Sheet 21 of 27 US 2017/0020926 A1 NoHA tag Yes HA tag O.O11% 0.017% 0.006% 0.0176 roll ses-Kirir-es-s-s & 6.4(e.3 10 1O 10 10 10 106 BL1-H: BL 1-H BL1-H: BL 1-H CFSE Fig 8A 28 8. 8. s si SCO ityye mir -- No Ceis - - No Surface Capture vases. With Surface Capture Fig 8B Patent Application Publication Jan. 26, 2017. Sheet 22 of 27 US 2017/0020926 A1 No Biotinylation Yes Biotinylation 5 E 10 wO 4.$3 iE 10°."19. C 2 10 S 10' 0.877 99.1 *xross-ressessers-s-typer-r102 10 x-rrysgress-s-s106 s: 102so: as x t 10s? 9 : 3 xSix:106 BL 1-H: BL 1-H BL 1-H: BL1-H CFSE Fig 8C si {{ s 8: Time mir -0- No Cells No Surface Capture ver, with Surface Capture Fig 8D Patent Application Publication Jan. 26, 2017. Sheet 23 of 27 US 2017/0020926 A1 rever-ressessesserteger-ses cOshu RBC 1 O O y 10 Cultured 80 V w W Cultured + intraCell. Prot mam Cultured + Surf Prot hours post-injection Fig 9B Jan. 26, 2017. Sheet 24 of 27 US 2017/0020926 A1 (u/au) Suoleuueouoo Patent Application Publication Jan. 26, 2017. Sheet 25 of 27 US 2017/0020926 A1 Time (hours) Fig 11A Time post-injection Cells + Intracell. Prot. Recombinant Protein Anti-HAWestern Blot Fig 11B Patent Application Publication Jan. 26, 2017. Sheet 26 of 27 US 2017/0020926 A1 **** Fig 12A - Transgene +Transgene 1724 8.21 88.1 29 2.34 1.
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    INFLAMMATION-DERIVED GROWTH FACTORS Optic nerve regeneration is becoming a reality. BY YUQIN YIN, MD, PHD; AND LARRY I. BENOWITZ, PHD ptic nerve trauma, ischemia, and or RAGs) in a pattern similar to that seen mannose, which is abundant in the vit- certain degenerative eye diseases during peripheral nerve regeneration.3 reous and cerebrospinal fluid, stimulates can lead to permanent vision Genetic deletion of two receptors appreciable axon growth from goldfish Oloss due to the inability of retinal that are expressed by inflammatory cells, RGCs and moderate outgrowth from rat ganglion cells (RGCs) to regenerate the Toll-like receptor 2 (TLR2) and dectin-1, RGCs. These effects require elevation of axons that convey visual information eliminates the proregenerative effects of cAMP and are strongly augmented by from the eye to the brain and the sub- zymosan, despite not altering the general a protein secreted by activated macro- sequent death of RGCs. Over the past profile of infiltrative cells.4 β-glucan is a phages.2,8 Using column chromatogra- 20 years, considerable progress has been component of zymosan that stimulates phy, mass spectrometry, and bioassays, made in defining factors that promote cells of the innate immune system via we identified the 11 kDa Ca2+-binding or suppress axon regeneration and RGC dectin-1, and curdlan, a particulate form protein oncomodulin (Ocm) as a major survival after optic nerve injury. of β-glucan, mimics the effects of zymo- growth-promoting factor associated This article describes research from san on regeneration.4 with inflammation.9 our lab that has identified trophic fac- Combining intraocular inflammation Ocm is secreted by infiltrative neutro- tors derived from inflammatory cells with elevation of cAMP and PTEN dele- phils and macrophages, and it accumu- that promote appreciable levels of tion in RGCs and other cells infected lates in the neural retina 12 to 24 hours optic nerve regeneration.
  • S41419-021-03972-6.Pdf

    S41419-021-03972-6.Pdf

    www.nature.com/cddis ARTICLE OPEN Primed to die: an investigation of the genetic mechanisms underlying noise-induced hearing loss and cochlear damage in homozygous Foxo3-knockout mice ✉ Holly J. Beaulac1,3, Felicia Gilels1,4, Jingyuan Zhang1,5, Sarah Jeoung2 and Patricia M. White 1 © The Author(s) 2021 The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/−), and Foxo3 knock-out (Foxo3−/−) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and caspase-independent apoptosis. Lower immunoreactivity of the calcium buffer Oncomodulin in Foxo3−/− OHCs correlated with cell loss beginning 4 h post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3−/− mice that may contribute to OHC noise susceptibility. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea.