# US 2014/0193378 A1 · Ghrh agonists for islet cell transplantation and function and the treatment of diabetes

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- Number: US 2014/0193378 A1
- Document ID: US20140193378A1
- Status: Published application
- Kind: A1
- Application number: 14/138,912
- Filed: 2013-12-23
- Published: 2014-07-10
- Earliest claimed: 2012-12-21
- Assignees: University of Miami; Dresden University of Technology; U.S.A., Represented By the Department of Veterans Affairs
- Applicants: University of Miami; Dresden University of Technology; U.S.A., Represented By the Department of Veterans Affairs
- Inventors: Andrew V. SCHALLY; Norman L. BLOCK; Stefan BORNSTEIN; Barbara LUDWIG
- Web page: https://patentgrep.com/patent/US20140193378A1

## CPC

- A61K 35/39: Pancreas; Islets of Langerhans (Langerhans cells of epidermis A61K35/36)
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 38/25: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
- C07K 14/60: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Disclosed herein are compositions of GHRH agonists and peptides, and methods to treat diabetes. In one embodiment, a method of promoting survival of grafted cells and/or tissues may involve exposing the cells and/or tissues to an effective amount of at least one agonist of GHRH. In some embodiments, the grafted cells and/or tissues may be pancreatic cells. In some embodiments, the grafted cells may be islet cells co-cultured with non-pancreatic cells. In a further embodiment, a method of treating a patient diagnosed with diabetes involves transplanting and/or grafting the islet cells and/or tissues comprising islet cells into a patient, and administering a therapeutically effective amount of at least one agonist of GHRH to the patient. In some embodiments, the islet cells and/or tissues comprising islet cells may be optionally exposed to GHRH and/or at least one agonist of GHRH prior to transplantation into a patient. In some embodiments, the at least one agonist of GHRH is administered pre-transplantation, concurrently with transplantation, post-transplantation or any combinations thereof.

## Claims

### Claim 1

A method of treating a patient diagnosed with diabetes comprising:
transplanting a tissue comprising islet cells into a patient; and
administering a therapeutically effective amount of a GHRH agonist peptide to the patient, wherein the GHRH agonist peptide has the formula:
[R1-A1-A2-Asp-Ala-Ile-A6-Thr-A8-Ser-Tyr-A11-A12-Val-Leu-A15-Gln-Leu-Ser-Ala-A20-A21-A22-Leu-Gln-Asp-Ile-Nle27-A28-A29-A30]-R2,
wherein R1 is Ac, Tfa, or is absent,
A1 is Tyr, Dat, or N-Me-Tyr,
A2 is Ala, D-Ala, Abu, or D-Abu,
A6 is Phe or Fpa5,
A8 is Asn, Ala, Gln, Thr, or N-Me-Ala,
A11 is Arg, His, or Har,
A12 is Orn, or Lys(Me)2,
A15 is Abu or Ala,
A20 is Arg, His, or Har,
A21 is Orn, or Lys(Me)2,
A22 is Leu, or Orn,
A28 is Ser, or Asp,
A29 is Arg, Har, Agm, D-Arg, or D-Har,
A30 is Arg, Agm, Ada, Amc, Aha, Apa, Har, D-Arg, D-Har, Gab, Gln, D-Gln, Gln-Gab, D-Gln-Gab, or is absent,
R2 is —NH2, —NH—CH3, NH—CH2—CH3, —OH, —NHR3, —N(R3)2, or —OR3, wherein R3 is any of C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl,
and pharmaceutically acceptable salts thereof, and wherein the agonist peptide is different from SEQ ID NO: 1 in at least one amino acid residue.

### Claim 2 (depends on 1)

The method of claim 1, wherein the tissue comprising islet cells are optionally exposed to the GHRH agonist peptide prior to transplantation into a patient.

### Claim 3 (depends on 1)

The method of claim 1, wherein the peptide is administered pre-transplantation, concurrently with transplantation, post-transplantation, or any combinations thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the GHRH agonist peptide is selected from the group having the formula:
P-20103 [N-Me-Tyr1, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2(SEQ ID NO: 2);
P-20105 [N-Me-Tyr1, D-Ala2, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20107 [N-Me-Tyr1, Fpa56, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 3);
P-20109 [N-Me-Tyr1, D-Ala2, Fpa56, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20110 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Agm29]hGHRH(1-29)NH2;
P-20111 [N-Me-Tyr1, D-Ala2, Fpa56, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20113 [N-Me-Tyr1, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 4);
P-20115 [N-Me-Tyr1, Fpa56, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 5);
P-20117 [N-Me-Tyr1, D-Ala2, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27, Agm29]hGHRH(1-29) NH2;
P-20350 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20351 [Ac-N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20356 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 6);
P-20357 [Dat1, D-Ala2, N-Me-Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20358 [N-Me-Tyr1, D-Ala2, N-Me-Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20359 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20360 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20361 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agrn29]hGHRH(1-29)NH2;
P-20367 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20370 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 7);
P-20371 [N-Me-Tyr1, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 8);
P-20372 [N-Me-Tyr1, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 9);
P-20373 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 10);
P-20374 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 11);
P-20375 [N-Me-Tyr1, Thr8, Orn12, Abu15, Orn21, Nle27, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 12);
P-20376 [N-Me-Tyr1, Ala8, Orn12, Abu15, Orn21, Nle27, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 13);
P-21300 [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21301 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2 (SEQ ID NO: 14);
P-21303 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21304 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21305 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21306 [Dat1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21307 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21308 [Dat1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21309 [N-Me-Tyr1, D-Ala2, Orn12, Ala8, Abu15, Orn21, Nle27, Asp28, Amc30]hGH-RH(1-30)NH2;
P-21310 [Dat1-D-Ala2, His11, Orn12, Abu15, His20, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-21311 [N-Me-Tyr1, D-Ala2, His11, Orn12, Abu15, His20, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH2;
P-22325 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2 (SEQ ID NO: 15);
P-22326 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2;
P-22327 [Dat1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2 (SEQ ID NO: 16);
P-22328 [Ac-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2;
P-22329 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Apa30]hGHRH(1-30)NH2;
P-22330 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2;
P-22331 [N-Me-Tyr1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2;
P-22332 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2 (SEQ ID NO: 17);
P-22334 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Apa30]hGHRH(1-30)NH2 (SEQ ID NO: 18);
P-22335 [N-Me-Tyr1, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2 (SEQ ID NO: 19);
P-22336 [N-Me-Tyr1 Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2 (SEQ ID NO: 20);
P-22337 [N-Me-Tyr1, D-Ala2, Cpa6, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH2;
P-23250 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23251 [Dat1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 21);
P-23252 [Dat1-D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23253 [Dat1, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 22);
P-23254 [Dat1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23255 [Dat1, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 23);
P-23256 [Dat1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23257 [Dat1, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 24);
P-23258 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23259 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 25);
P-23260 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23261 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 26);
P-23262 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23263 [N-Me-Tyr1, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 27);
P-23264 [N-Me-Tyr1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2;
P-23265 [N-Me-Tyr1, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH2 (SEQ ID NO: 28);
P-24340 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2 (SEQ ID NO: 29);
P-24341 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2;
P-24342 [Dat1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2 (SEQ ID NO: 30);
P-24344 [Dat1-D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2;
P-24345 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2;
P-24346 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Aha30]hGHRH(1-30)NH2;
P-24347 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2;
P-24348 [N-Me-Tyr1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH2;
P-25501 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2;
P-25502 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2;
P-25503 [N-Me-Tyr1, Abu2, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2 (SEQ ID NO: 31);
P-25504 [Dat1, D-Abu2, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2;
P-25506 [N-Me-Tyr1, D-Abu2, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30) NH2;
P-25508 [Tfa-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2;
P-25516 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Gab30]hGHRH(1-30)NH2;
P-26802 [Dat1, D-Ala2, Thr8, His11, Orn12, Abu15, His20, Orn21, Nle27, Ada30]hGHRH(1-30)NH2;
P-26803 [N-Me-Tyr1, D-Ala2, Gln8, His11, Orn12, Abu15, His20, Orn21, Nle27, Ada30]hGHRH(1-30)NH—CH3;
P-26804 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Ada30]hGHRH(1-30)NH2;
P-27400 [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27401 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27403 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27404 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27405 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH3 (SEQ ID NO: 32);
P-27406 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 33);
P-27407 [Dat1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 34);
P-27408 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-30)NH—CH3;
P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27410 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27411 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH3;
P-27412 [N-Me-Tyr1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27413 [Dat1, Gln8, His11, Orn12, Abu15, His20, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 35);
P-27414 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH—CH3;
P-27415 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH—CH3 (SEQ ID NO: 36);
P-27416 [N-Me-Tyr1, D-Ala2, Gln8, His11, Orn12, Abu15, His20, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27417 [Ac-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27418 [Ac-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27419 [Ac-Tyr1, Thr8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH3 (SEQ ID NO: 37);
P-27422 [N-Me-D-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27423 [N-Me-D-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27424 [Dat1, Thr8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH3 (SEQ ID NO: 38);
P-27425 [N-Me-D-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27440 [Dat1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27441 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27442 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27443 [N-Me-Tyr1, Orn12, Abu15, Orn21, Nle27, D-Arg29]hGHRH(1-29)NH—CH3;
P-27444 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27445 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27446 [N-Me-Tyr1, D-Ala2, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, D-Arg29]hGHRH(1-29)NH—CH3;
P-27447 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH—CH3;
P-27448 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH—CH3;
P-27449 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH—CH3;
P-27450 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH—CH3;
P-27451 [N-Me-Tyr1, D-Ala2, Gln8, His11, Orn12, Abu15, His20, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH—CH3;
P-28420 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28421 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29) NH—CH2—CH3;
P-28430 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH2—CH3;
P-28431 [N-Me-Tyr1, D-Ala2, Thr8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28460 [N-Me-Tyr1, D-Ala2, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28461 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29) NH—CH2—CH3;
P-28462 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29) NH—CH2—CH3;
P-28463 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH2—CH3;
P-28464 [N-Me-Tyr1, D-Ala2, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH2—CH3;
P-28465 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28466 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28467 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28468 [N-Me-Tyr1, D-Ala2, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28469 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH2—CH3;
P-28470 [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27]hGHRH(1-29)NH—CH2—CH3;
P-28471 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28472[Dat1, D-Ala2, Fpa56, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28473 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28474 [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28475 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH—CH2—CF13;
P-28476 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Aha30]hGHRH(1-30)NH—CH2—CH2;
P-28477 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Amc30]hGHRH(1-30)NH—CH2—CH3;
P-28478 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Har30]hGHRH(1-30)NH—CH2—CH13;
P-28479 [N-Me-Tyr1, D-Ala2, Gln8, His11, Orn12, Abu15, His20, Orn21, Nle27, Asp28, Apa30]hGHRH(1-30)NH—CH2—CH3;
P-29701 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Gln-Gab30]hGHRH](1-30)NH2;
P-29702 [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Gln-Gab30]hGHRH(1-30)NH2;
P-29703 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Gln-Gab30]hGHRH(1-30)NH2 (SEQ ID NO: 39);
P-29704 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn21,22, Nle27, Gln-Gab30]hGHRH(1-30)NH2;
P-29706 [Tfa-Tyr1, D-Abu2, Gln8, Orn12, Abu15, Orn21, Nle27, Gln-Gab30]hGHRH(1-30)NH2;
P-29708 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gln-Gab30]hGHRH(1-30)NH2;
P-29710 [N-Me-Tyr1, D-Ala2, Fpa56, Ala8, Orn12, Abu15, Orn21, Nle27, Gln-Gab30]hGHRH(1-30)NH2;
P-29720 [Dat1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Gln-Gab30]hGHRH(1-30)NH2;
P-29721 [Dat1, D-Ala2, Gln8, Orn12, Abu15, Orn2122, Nle27, Asp28, Gln-Gab30]hGHRH(1-30)NH2;
P-29722 [Tfa-Tyr1, D-Abu2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Gln30, Gab31]hGHRH(1-30)NH2;
P-29723 [N-Me-Tyr1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Asp28, Gln-Gab30]hGHRH(1-30)NH2; and
P-29724 [N-Me-Tyr1, D-Ala2, Fpa56, Ala8, Orn12, Abu15, Orn21, Nle27, Asp28, Gln Gab30]hGHRH(1-30)NH2.

### Claim 5 (depends on 1)

The method of claim 1, wherein GHRH agonist peptide is selected from the group having the formula:
P-20367 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20361 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agrn29]hGHRH(1-29)NH2;
P-27406 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 33);
P-28420 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28421 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29) NH—CH2—CH3;
P-27403 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-20356 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 6); and
P-25502 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2.

### Claim 6 (depends on 1)

The method of claim 1, wherein the GHRH agonist peptide is:
P-27403 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3.

### Claim 7 (depends on 1)

The method of claim 1, wherein the GHRH agonist peptide is:
P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3.

### Claim 8 (depends on 1)

The method of claim 1, wherein the GHRH agonist peptide is:
P-20356 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 6).

### Claim 9 (depends on 1)

The method of claim 1, wherein the GHRH agonist peptide is:
P-25502 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2.

### Claim 10

A method of promoting survival of grafted tissue, the method comprising exposing the tissue to an effective amount of a GHRH agonist peptide, wherein the GHRH agonist peptide has the formula:
[R1-A1-A2-Asp-Ala-Ile-A6-Thr-A8-Ser-Tyr-A11-A12-Val-Leu-A15-Gln-Leu-Ser-Ala-A20-A21-A22-Leu-Gln-Asp-Ile-Nle27-A28-A29-A30]-R2,
wherein R1 is Ac, Tfa, or is absent,
A1 is Tyr, Dat, or N-Me-Tyr,
A2 is Ala, D-Ala, Abu, or D-Abu,
A6 is Phe or Fpa5,
A8 is Asn, Ala, Gln, Thr, or N-Me-Ala,
A11 is Arg, H is, or Har,
A12 is Orn, or Lys(Me)2,
A15 is Abu or Ala,
A20 is Arg, His, or Har,
A21 is Orn, or Lys(Me)2,
A22 is Leu, or Orn,
A28 is Ser, or Asp,
A29 is Arg, Har, Agm, D-Arg, or D-Har,
A30 is Arg, Agm, Ada, Amc, Aha, Apa, Har, D-Arg, D-Har, Gab, Gln, D-Gln, Gln-Gab, D-Gln-Gab, or is absent,
R2 is —NH2, —NH—CH3, NH—CH2—CH3, —OH, —NHR3, —N(R3)2, or —OR3, wherein R3 is any of C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl,
and pharmaceutically acceptable salts thereof, and wherein the agonist peptide is different from SEQ ID NO: 1 in at least one amino acid residue.

### Claim 11 (depends on 10)

The method of claim 10, wherein the grafted tissue proliferate and repopulate damaged tissues in vivo.

### Claim 12 (depends on 10)

The method of claim 10, wherein the grafted tissue comprises pancreatic cells.

### Claim 13 (depends on 10)

The method of claim 10, wherein the grafted tissue comprises pancreatic cells co-cultured with non-pancreatic cells.

### Claim 14 (depends on 10)

The method of claim 10, wherein GHRH agonist peptide is selected from the group having the formula:
P-20367 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20361 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agrn29]hGHRH(1-29)NH2;
P-27406 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 33);
P-28420 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28421 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-27403 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-20356 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 6); and
P-25502 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2.

### Claim 15

A method of modulating a function of an insulin producing cell, the method comprising exposing the insulin producing cell to an effective amount of a GHRH agonist peptide, wherein the GHRH agonist peptide comprises a formula:
[R1-A1-A2-Asp-Ala-Ile-A6-Thr-A8-Ser-Tyr-A11-A12-Val-Leu-A15-Gln-Leu-Ser-Ala-A20-A21-A22-Leu-Gln-Asp-Ile-Nle27-A28-A29-A30]R2,
wherein R1 is Ac, Tfa, or is absent,
A1 is Tyr, Dat, or N-Me-Tyr,
A2 is Ala, D-Ala, Abu, or D-Abu,
A6 is Phe or Fpa5,
A8 is Asn, Ala, Gln, Thr, or N-Me-Ala,
A11 is Arg, His, or Har,
A12 is Orn, or Lys(Me)2,
A15 is Abu or Ala,
A20 is Arg, His, or Har,
A21 is Orn, or Lys(Me)2,
A22 is Leu, or Orn,
A28 is Ser, or Asp,
A29 is Arg, Har, Agm, D-Arg, or D-Har,
A30 is Arg, Agm, Ada, Amc, Aha, Apa, Har, D-Arg, D-Har, Gab, Gln, D-Gln, Gln-Gab, D-Gln-Gab, or is absent,
R2 is —NH2, —NH—CH3, NH—CH2—CH3, —OH, —NHR3, —N(R3)2, or —OR3, wherein R3 is any of C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl,
and pharmaceutically acceptable salts thereof, and wherein the agonist peptide is different from SEQ ID NO: 1 in at least one amino acid residue.

### Claim 16 (depends on 15)

The method of claim 15, wherein the insulin producing cell comprises an islet cell.

### Claim 17 (depends on 15)

The method of claim 15, wherein the insulin producing cell comprises a cell expressing a recombinant insulin molecule.

### Claim 18 (depends on 17)

The method of claim 17, wherein the cell expressing the recombinant insulin molecule comprises a stem cell, a pancreatic cell, a transformed cell, a microbe or a cell sensitive to GHRH.

### Claim 19 (depends on 15)

The method of claim 15, wherein GHRH agonist peptide is selected from the group having the formula:
P-20367 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20361 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agrn29]hGHRH(1-29)NH2;
P-27406 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 33);
P-28420 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28421 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-27403 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-20356 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 6); and
P-25502 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2.

### Claim 20

A method of transplanting insulin producing cells into a diabetic mammal in need thereof, the method comprising:
transplanting the insulin producing cells into an adrenal gland of the diabetic mammal; and
administering a therapeutically effective amount of a GHRH agonist peptide to the diabetic mammal, wherein the GHRH agonist peptide comprises a formula:
[R1-A1-A2-Asp-Ala-Ile-A6-Thr-A8-Ser-Tyr-A11-A12-Val-Leu-A15-Gln-Leu-Ser-Ala-A20-A21-A22-Leu-Gln-Asp-Ile-Nle27-A28-A29-A30]-R2,
wherein R1 is Ac, Tfa, or is absent,
A1 is Tyr, Dat, or N-Me-Tyr,
A2 is Ala, D-Ala, Abu, or D-Abu,
A6 is Phe or Fpa5,
A8 is Asn, Ala, Gln, Thr, or N-Me-Ala,
A11 is Arg, His, or Har,
A12 is Orn, or Lys(Me)2,
A15 is Abu or Ala,
A20 is Arg, His, or Har,
A21 is Orn, or Lys(Me)2,
A22 is Leu, or Orn,
A28 is Ser, or Asp,
A29 is Arg, Har, Agm, D-Arg, or D-Har,
A30 is Arg, Agm, Ada, Amc, Aha, Apa, Har, D-Arg, D-Har, Gab, Gln, D-Gln, Gln-Gab, D-Gln-Gab, or is absent,
R2 is —NH2, —NH—CH3, NH—CH2—CH3, —OH, —NHR3, —N(R3)2, or —OR3, wherein R3 is any of C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl,
and pharmaceutically acceptable salts thereof, and wherein the agonist peptide is different from SEQ ID NO: 1 in at least one amino acid residue.

### Claim 21 (depends on 20)

The method of claim 20, wherein the insulin producing cells are optionally exposed to the GHRH agonist peptide prior to transplantation into the diabetic mammal.

### Claim 22 (depends on 20)

The method of claim 20, wherein the peptide is administered pre-transplantation, concurrently with transplantation, post-transplantation, or any combinations thereof.

### Claim 23 (depends on 20)

The method of claim 20, wherein GHRH agonist peptide is selected from the group having the formula:
P-20367 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-20361 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2;
P-27406 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3 (SEQ ID NO: 33);
P-28420 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH2—CH3;
P-28421 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29) NH—CH2—CH3;
P-27403 [N-Me-Tyr1, D-Ala2, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-27409 [N-Me-Tyr1, D-Ala2, Orn12, Abu15, Orn21, Nle27, Asp28]hGHRH(1-29)NH—CH3;
P-20356 [N-Me-Tyr1, Gln8, Orn12, Abu15, Orn21, Nle27, Asp28, Agm29]hGHRH(1-29)NH2 (SEQ ID NO: 6); and
P-25502 [Dat1, D-Ala2, Fpa56, Orn12, Abu15, Orn21, Nle27, Gab30]hGHRH(1-30)NH2.