Methods and compositions for modulating PD1
Disclosed herein are methods and compositions for modulating expression of a PD1 gene.
1. A method of repressing PD1 expression in a human T-cell cell of a subject having a disease or disorder characterized by aberrant expression or regulation of a PD1 gene, the method comprising
repressing expression of the PD1 gene in an isolated T-cell by administering a polynucleotide encoding a fusion protein comprising a zinc finger protein and a functional domain to the cell, wherein the zinc finger protein comprises four, five or six zinc finger recognition regions ordered from F1 to F4, F1 to F5 or F1 to F6, from N-terminus to C-terminus, and wherein the recognition regions comprise the following amino acid sequences:
(i)
(SEQ ID NO: 1)
F1: QSGHLSR,
(SEQ ID NO: 2)
F2: RSDSLSV,
(SEQ ID NO: 3)
F3: HNDSRKN,
(SEQ ID NO: 4)
F4: RSDDLTR,
and
(SEQ ID NO: 5)
F5: RSDHLTQ;
(ii)
(SEQ ID NO: 6)
F1: RSAALSR,
(SEQ ID NO: 4)
F2: RSDDLTR,
(SEQ ID NO: 7)
F3: RSDHLTT,
(SEQ ID NO: 8)
F4: DRSALSR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(iii)
(SEQ ID NO: 10)
F1: RSAALAR,
(SEQ ID NO: 11)
F2: RSDDLSK,
(SEQ ID NO: 12)
F3: RNDHRKN,
(SEQ ID NO: 8)
F4: DRSALSR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(iv)
(SEQ ID NO: 13)
F1: RSDHLSE,
(SEQ ID NO: 14)
F2: TSSDRTK,
(SEQ ID NO: 13)
F3: RSDHLSE,
and
(SEQ ID NO: 15)
F4: QSASRKN;
(v)
(SEQ ID NO: 16)
F1: RSDVLSE,
(SEQ ID NO: 17)
F2: RSANLTR,
(SEQ ID NO: 18)
F3: RSDHLSQ,
(SEQ ID NO: 19)
F4: TSSNRKT,
(SEQ ID NO: 20)
F5: DRSNLSR,
and
(SEQ ID NO: 21)
F6: RSDALAR;
or
(vi)
(SEQ ID NO: 22)
F1: DDWNLSQ,
(SEQ ID NO: 17)
F2: RSANLTR,
(SEQ ID NO: 18)
F3: RSDHLSQ,
(SEQ ID NO: 19)
F4: TSSNRKT,
(SEQ ID NO: 20)
F5: DRSNLSR,
and
(SEQ ID NO: 21)
F6: RSDALAR;
(vii)
(SEQ ID NO: 23)
F1: RSSALSR,
(SEQ ID NO: 24)
F2: RPLALKH,
(SEQ ID NO: 12)
F3: RNDHRKN,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(viii)
(SEQ ID NO: 1)
F1: QSGHLSR,
(SEQ ID NO: 2)
F2: RSDSLSV,
(SEQ ID NO: 3)
F3: HNDSRKN,
(SEQ ID NO: 26)
F4: RANSLLR,
and
(SEQ ID NO: 5)
F5: RSDHLTQ;
(ix)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 29)
F3: RNNNLRT,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(x)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 30)
F3: TNWHLRT,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xi)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 31)
F3: RTPHLTL,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xii)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 32)
F3: RSAQLAT,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xiii)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 33)
F3: RCTHLYL,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xiv)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 34)
F3: RPTQRYS,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xiv)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 35)
F3: RANHREC,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xvi)
(SEQ ID NO: 36)
F1: RKFARPS,
(SEQ ID NO: 37)
F2: RNFSRSD,
(SEQ ID NO: 38)
F3: HPHHRMC,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xvii)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 39)
F3: RMGRLST,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xviii)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 40)
F3: RHSRLTT,
(SEQ ID NO: 41)
F4: TRPVLMR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xix)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 42)
F3: RANHRVC,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xx)
(SEQ ID NO: 27)
F1: RPSTLHR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 43)
F3: RSTHLLG,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxi)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR
(SEQ ID NO: 44)
F3: RSCGLWS
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxii)
(SEQ ID NO: 46)
F1: CNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 47)
F3: REEHRAT,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxiii)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 48)
F3: RHHHLAA,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxiv)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 49)
F3: RPMHLTN,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxv)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 50)
F3: RSPHLYH,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxvi)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 51)
F3: RCEALHH,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 52)
F5: DRSAQAR;
(xxvii)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 51)
F3: RCEALHH,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
(xxviii)
(SEQ ID NO: 45)
F1: RNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 53)
F3: RLPALLS,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
or
(xxix)
(SEQ ID NO: 54)
F1: HNAALTR,
(SEQ ID NO: 28)
F2: RSDELTR,
(SEQ ID NO: 55)
F3: RTYNRTQ,
(SEQ ID NO: 25)
F4: TRPVLKR,
and
(SEQ ID NO: 9)
F5: DRSALAR;
and
administering the cell to the subject.
2. The method of claim 1 , wherein the fusion protein comprises a transcriptional repression domain.
3. The method of claim 1 , wherein the fusion protein comprises a cleavage domain.
4. The method of claim 1 , wherein the disease or disorder is a cancer or a viral infection.
5. The method of claim 4 , further comprising administering an anti-viral or anti-cancer therapy to the subject.
6. The method of claim 5 , wherein the anti-viral or anti-cancer therapy are administered prior to, concurrently or sequentially with the cell.
7. The method of claim 1 , wherein the cell is a CD4+ T-cell.