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Dr. Trauner is actively seeking pharmaceutical company partners to develop 24-nor-ursodeoxycholic acid as a potential cure for sclerosing cholangitis, as outlined in this one page publication:

24-nor-Ursodeoxycholic Acid - Substance for curing Sclerosing Cholangitis and Cholestatic Liver Disease

http://www.meduni-graz.at/images/content/file/forschung/kooperationen/081014_TO_NorUrso_liver.pdf

Prof. Dr. Trauner, Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine

BACKGROUND

Current medical treatment for human primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease representing an important indication for liver transplantation and cause of liver-related death, is of limited efficacy. Multidrug resistance gene 2 (Mdr2/Abcb4) knockout mice (Mdr2-/-) represent a well characterized model for sclerosing cholangitis. We aimed to test the therapeutic effects of 24-nor-ursodeoxycholic acid (norUDCA), a side chain-modified UDCA derivative undergoing cholehepatic shunting) in Mdr2-/-.

METHODS2-months-old Mdr2-/- received standard chow (controls) or 0.5% norUDCA-supplemented diet or 0.5% UDCA-supplemented diet for 4 weeks. Effects on serum liver tests, liver histology, markers of inflammation and fibrosis, and bile acid transporters and detoxification enzymes were compared.

RESULTSnorUDCA significantly improved serum liver tests (ALT 165 +/- 23 vs. 405 +/- 187 IU in controls; p < 0.05; AP 235 +/- 55 vs. 162 +/- 25; p < 0.05) and liver histology, reduced hydroxyproline content (124 +/- 16 vs. 229 +/- 94 mg/g liver; p < 0.05), infiltrating neutrophils (2 +/- 1 vs. 20 +/- 5/portal field; p < 0.05) and proliferating Ki-67-positive hepatocytes (0.7 +/- 0.9 vs. 39+/- 15/high power field; p < 0.05), stimulated biliarybicarbonate excretion (99 +/- 14 vs. 61 +/- 8 nmol/g liver weight/min; p < 0.05) and resulted in coordinated induction of sulfotransferase Sult2a1 and bile acid sulfate efflux pump Mrp4 together with urinary bile acid sulfate excretion. UDCA significantly increased ALT and AP levels, had no signifi cant effects on hydroxyproline content and bicarbonate excretion, and weaker effects on biliary transporters and enzymes.

CONCLUSIONSnorUDCA cures sclerosing cholangitis in Mdr2-/-. Its therapeutic mechanisms likely involve (i) flushing of injured bile ducts by bicarbonate-induced choleresis, (ii) induction of alternative detoxification and elimination routes for bile acids and (iii) antiinfl ammatory as well as (vi) antifibrotic properties.

SUMMARYNor-UDCA > reduces liver injury > reduces fibrosis > reduces inflammation> reduces TIMP1 expression > induces bicarbonate secretion > induces adaptive transporter and metabolic response.Nor-UDCA cures sclerosing cholangitis in Mdr2-/-mice.Nor-UDCA may represent a novel treatment option for PSC and PBC.

October 2008

24-nor-Ursodeoxycholic Acid - Substance for curing Sclerosing Cholangitis and Cholestatic Liver Disease Technology Offer

CONTACTDr. Margit LachmannMedical University of GrazTechnology Transfer OfficeAuenbruggerplatz 2A-8036 Grazphone: +43-7e-mail: margit.lachmann@...

Figure 1: norUDCA cures sclerosing cholangitis in Mdr2-/- mice.(A) Liver histology (H & E staining) in control diet-fed Mdr2-/- mice(KO), UDCA-fed Mdr2-/- mice (KO+UDCA), and norUDCA-fedMdr2-/- mice (KO+norUDCA) (Magnification x 10). Pronouncedlarge bile duct disease in KO (arrow heads) which is significantly reducedin KO+UDCA (arrow heads) and absent in KO+norUDCA. (B)Sclerosing cholangitis in KO with periductal fibrosis, alterated bileduct epithelial cells and mixed inflammatory infiltrate. This featuresare ameliorated in KO+UDCA and absent in KO+norUDCA (Magnificationx 40). © Sirius red staining showing signifi cant fibrosis withperiductal collagen fibers (red) in KO. Moderate reduction of fibrosisin KO+UDCA and even more pronounced reduction in KO+norUDCA(Magnification for b, c x 40); bd, bile duct.

Figure 2: Suggested therapeutic mechanisms of norUDCA in Mdr2-/-mice: norUDCA is taken up by hepatocytes and secreted into canaliculiand bile ducts where it is taken up by cholangiocytes leadingto ductular bicarbonate secretion. norUDCA is secreted backinto the peribiliary plexus and shunted back to the hepatocytes(cholehepatic shunting). NorUDCA induces expression of Sult2a1etc. and Mrp3 and Mrp4 which detoxifies bile salts and makes themamenable for renal elimination.

COLLABORATION DETAILSCollaboration can be in the form of alicense agreement or a technical researchcooperation for clinical development ofNorUDCA in USA.

POSSIBLE PARTNERSPharma

DEVELOPMENT STATUSpreclinical studiespatent pending

Dave

(father of (23); PSC 07/03; UC 08/03)

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This news seems very postive although I try not to get to excited, but it is hard not to after reading the words "norUDCA cures sclerosing cholangitis in Mdr2-/-.". The question I would have is there anyway to help move this along to get it into the US and Canada in a fairly rapid fashion?

I would love to walk into my GI's office tomorrow and ask for a perscription, but it sounds like there is no drug company making this type of product yet. Does anyone know how long this process takes? I know sometimes it can be years before something goes through clinical trials to finally making it to public availability.

Either way this news is very encouraging to say the least!

-Dave, BC, Canada

(PSC, 2007)

Subject: 24-nor-Ursodeoxycholic Acid UpdateTo: Date: Sunday, December 21, 2008, 9:39 PM

Dr. Trauner is actively seeking pharmaceutical company partners to develop 24-nor-ursodeoxycho lic acid as a potential cure for sclerosing cholangitis, as outlined in this one page publication:

24-nor-Ursodeoxycho lic Acid - Substance for curing Sclerosing Cholangitis and Cholestatic Liver Disease

http://www.meduni- graz.at/images/ content/file/ forschung/ kooperationen/ 081014_TO_ NorUrso_liver. pdf

Prof. Dr. Trauner, Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine

BACKGROUND

Current medical treatment for human primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease representing an important indication for liver transplantation and cause of liver-related death, is of limited efficacy. Multidrug resistance gene 2 (Mdr2/Abcb4) knockout mice (Mdr2-/-) represent a well characterized model for sclerosing cholangitis. We aimed to test the therapeutic effects of 24-nor-ursodeoxycho lic acid (norUDCA), a side chain-modified UDCA derivative undergoing cholehepatic shunting) in Mdr2-/-.

METHODS2-months-old Mdr2-/- received standard chow (controls) or 0.5% norUDCA-supplemente d diet or 0.5% UDCA-supplemented diet for 4 weeks. Effects on serum liver tests, liver histology, markers of inflammation and fibrosis, and bile acid transporters and detoxification enzymes were compared.

RESULTSnorUDCA significantly improved serum liver tests (ALT 165 +/- 23 vs. 405 +/- 187 IU in controls; p < 0.05; AP 235 +/- 55 vs. 162 +/- 25; p < 0.05) and liver histology, reduced hydroxyproline content (124 +/- 16 vs. 229 +/- 94 mg/g liver; p < 0.05), infiltrating neutrophils (2 +/- 1 vs. 20 +/- 5/portal field; p < 0.05) and proliferating Ki-67-positive hepatocytes (0.7 +/- 0.9 vs. 39+/- 15/high power field; p < 0.05), stimulated biliarybicarbonate excretion (99 +/- 14 vs. 61 +/- 8 nmol/g liver weight/min; p < 0.05) and resulted in coordinated induction of sulfotransferase Sult2a1 and bile acid sulfate efflux pump Mrp4 together with urinary bile acid sulfate excretion. UDCA significantly increased ALT and AP levels, had no signifi cant effects on hydroxyproline content and bicarbonate excretion, and weaker effects on biliary transporters and enzymes.

CONCLUSIONSnorUDCA cures sclerosing cholangitis in Mdr2-/-. Its therapeutic mechanisms likely involve (i) flushing of injured bile ducts by bicarbonate- induced choleresis, (ii) induction of alternative detoxification and elimination routes for bile acids and (iii) antiinfl ammatory as well as (vi) antifibrotic properties.

SUMMARYNor-UDCA > reduces liver injury > reduces fibrosis > reduces inflammation> reduces TIMP1 expression > induces bicarbonate secretion > induces adaptive transporter and metabolic response.Nor-UDCA cures sclerosing cholangitis in Mdr2-/-mice.Nor-UDCA may represent a novel treatment option for PSC and PBC.

October 2008

24-nor-Ursodeoxycho lic Acid - Substance for curing Sclerosing Cholangitis and Cholestatic Liver Disease Technology Offer

CONTACTDr. Margit LachmannMedical University of GrazTechnology Transfer OfficeAuenbruggerplatz 2A-8036 Grazphone: +43-316-385- 72017e-mail: margit.lachmann@ meduni-graz. at

Figure 1: norUDCA cures sclerosing cholangitis in Mdr2-/- mice.(A) Liver histology (H & E staining) in control diet-fed Mdr2-/- mice(KO), UDCA-fed Mdr2-/- mice (KO+UDCA), and norUDCA-fedMdr2-/- mice (KO+norUDCA) (Magnification x 10). Pronouncedlarge bile duct disease in KO (arrow heads) which is significantly reducedin KO+UDCA (arrow heads) and absent in KO+norUDCA. (B)Sclerosing cholangitis in KO with periductal fibrosis, alterated bileduct epithelial cells and mixed inflammatory infiltrate. This featuresare ameliorated in KO+UDCA and absent in KO+norUDCA (Magnificationx 40). © Sirius red staining showing signifi cant fibrosis withperiductal collagen fibers (red) in KO. Moderate reduction of fibrosisin KO+UDCA and even more pronounced reduction in KO+norUDCA(Magnification for b, c x 40); bd, bile duct.

Figure 2: Suggested therapeutic mechanisms of norUDCA in Mdr2-/-mice: norUDCA is taken up by hepatocytes and secreted into canaliculiand bile ducts where it is taken up by cholangiocytes leadingto ductular bicarbonate secretion. norUDCA is secreted backinto the peribiliary plexus and shunted back to the hepatocytes(cholehepatic shunting). NorUDCA induces expression of Sult2a1etc. and Mrp3 and Mrp4 which detoxifies bile salts and makes themamenable for renal elimination.

COLLABORATION DETAILSCollaboration can be in the form of alicense agreement or a technical researchcooperation for clinical development ofNorUDCA in USA.

POSSIBLE PARTNERSPharma

DEVELOPMENT STATUSpreclinical studiespatent pending

Dave

(father of (23); PSC 07/03; UC 08/03)

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Merry Christmas !!Maybe this is the good news we have all been waiting for.I will start praying that this will be the solution we all want.Here's hoping nor-urso lives up to it's potential and more.Thanks so much for sharing this hopeful news, what a present.LeeDr. Trauner is actively seeking pharmaceutical company partners to develop 24-nor-ursodeoxycholic acid as a potential cure for sclerosing cholangitis, as outlined in this one page publication:24-nor-Ursodeoxycholic Acid - Substance for curing Sclerosing Cholangitis and Cholestatic Liver Diseasehttp://www.meduni-graz.at/images/content/file/forschung/kooperationen/081014_TO_NorUrso_liver.pdfProf. Dr. Trauner, Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine

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Merry Christmas !!Maybe this is the good news we have all been waiting for.I will start praying that this will be the solution we all want.Here's hoping nor-urso lives up to it's potential and more.Thanks so much for sharing this hopeful news, what a present.LeeDr. Trauner is actively seeking pharmaceutical company partners to develop 24-nor-ursodeoxycholic acid as a potential cure for sclerosing cholangitis, as outlined in this one page publication:24-nor-Ursodeoxycholic Acid - Substance for curing Sclerosing Cholangitis and Cholestatic Liver Diseasehttp://www.meduni-graz.at/images/content/file/forschung/kooperationen/081014_TO_NorUrso_liver.pdfProf. Dr. Trauner, Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine

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Hi ,

This does look really exciting but may I ask if you can simplify the

article for me (and others) as I really dont understand what half of it

means. sorry but I am blonde!!

Merry Christmas To All

(Uk. psc & uc 2002)

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Hi ,

This does look really exciting but may I ask if you can simplify the

article for me (and others) as I really dont understand what half of it

means. sorry but I am blonde!!

Merry Christmas To All

(Uk. psc & uc 2002)

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>This does look really exciting but may I ask if you can simplify the

article for me (and others) as I really dont understand what half of

it means.

Hi ;

O.K. I'll try my best to simplify it.....

The cells of the liver produce and secrete bile into the bile ducts

in order to help digest food. The secretion of bile into the bile

ducts depends on a number of different proteins on the surface of

liver cells. Defects in these proteins can disrupt bile flow and lead

to liver disease. One of the bile secreting proteins is the Mdr2

protein in mice (the equivalent protein in humans is the MDR3

protein). This protein helps to secrete phospholipids into the bile.

Researchers can disrupt this protein in mice by knocking out the gene

that encodes the protein. These " Mdr2 knock out " mice develop a liver

disease closely resembling primary sclerosing cholangitis.

Researchers like Trauner have been using these knockout mice

to try to find medicines that halt or reverse/cure the liver disease.

They find that ursodiol is somewhat effective, but not nearly as

effective in reversing and curing the disease as a slightly modified

version of ursodiol called 24-nor-urso. This modified urso is a

little bit smaller than urso, and seems to be less easily

metabolized, and circulates between the liver and intestine more

extensively. 24-nor-urso seems to reduce liver inflammation and

fibrosis, and looks very promising as a potential treatment for human

PSC. So Trauner (in Austria) is seeking a partnership with a

pharmaceutical company to try to develop 24-nor-urso as a medicine

that can be tested in clinical trials with PSC patients to see if it

delays progression of PSC and/or reverses/cures it.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

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Thanks for the link. I did some googling and discovered that Dr.

Trauner is also pursuing nor-UDCA research as a solution for

atheroscelerosis (you may remember a link you posted maybe a year

ago referencing his theory that atherosclerosis and PSC had

similarities).

Atherosclerosis research is almost certain to generate a lot more

interest from Big Pharma, given the much larger pool of clogged-

artery patients vis-a-vis PSCers.

Personally, I've been taking serrapeptase and nattokinase for about

six months now for their antifibrotic activity - they're primarily

marketed to people worried about their arteries. I can't say

whether they've helped or hurt; if there has been an effect it's

been pretty mild.

>

>

> Dr. Trauner is actively seeking pharmaceutical company

partners

> to develop 24-nor-ursodeoxycholic acid as a potential cure for

> sclerosing cholangitis, as outlined in this one page publication:

>

> 24-nor-Ursodeoxycholic Acid - Substance for curing Sclerosing

> Cholangitis and Cholestatic Liver Disease

>

> http://www.meduni-

graz.at/images/content/file/forschung/kooperationen/08\

> 1014_TO_NorUrso_liver.pdf

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