Some content of this application is unavailable at the moment.
If this situation persist, please contact us atFeedback&Contact
1. (WO2017037465) DIAGNOSTIC METHODS AND KITS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims

1 . A method for diagnosing or monitoring the progress of a condition caused by defective cholesterol biosynthesis, said method comprising detecting in a biological sample levels of delta-5 bile acid conjugated with 2-(acetylamino)-2-deoxy-D-glucose (GicNAc) of formula (I)


M i

or a derivative thereof or a recursor of any one of formulae (ll)-(Vii), or (XX)-(XXI



(XXII) (XXIII)

which are higher than those found in a sample from a subject not suffering from said condition.

2. A method according to claim 1 wherein the sample is a blood, plasma, serum, cerebrospinal fluid (CSF) or urine sample.

3. A method according to claim 1 or claim 2 wherein the levels of delta-5 bile acid GlcNAc of formula (I)

or a derivative thereof or a precursor thereof, which are higher than those found in a sample from a subject not suffering from said condition are detected in the biological sample,

4. A method according to claim 3 wherein a precursor of the compound of formula (I) is a compound of formula (II) to (VII), or (XX)-(XXIII)


5. A method according to ciaim 4 wherein the precursor compound of formuia (II)-(VII), (XX) or (XXI) is detected in a blood, serum, plasma or CSF sample.

6. A method according to claim 1 which comprises detecting levels of the compound of formula (I) or a derivative thereof, in a urine sample from a subject suspected of or suffering from SLOS or from a urine sample from an expectant mother.

7. A method according to claim 6 wherein the derivative of formula (I) is a compound of formula (X) or (XI)

wherein R is a hydroxy!, glycine or taurine group.

8. A method according to any one of the preceding claims which further comprises detecting and/or quantifying a further compound or diagnostic marker which is characteristic of a condition caused by defective cholesterol biosynthesis such as SLOS.

9. A method according to claim 8 wherein the level of 8-dehydocholesteroi (8-DHC) of formula (XIII)


or a metabolite thereof, selected from 24-hydroxy-8-DHG (24-OH-8-DHG) of formula (XIV), 25-OH-8-DHC of formula (XV) and 26-OH-8-DHC of formula (XVI),


is detected.

1 0. A method according to claim 9 wherein the level of the compound of formula (XIV) or (XV) is detected.

1 1 . A method according to any one of claims 8 to 10 wherein the level of 7-DHC of formula (IX)


(IX)

or 7-DHC metabolites are detected and compared with those found in a sample from a subject not suffering from said condition.

1 2. A method according to claim 1 1 wherein the 7-DHC metabolites are selected from 4-OH-7-DHC of formula (XVI I), 7-oxocholesterol (Compound VII I), 7 ,8 -epoxycholesterol (XVII I) and 3[3,5 -dihydroxycholest-7-en-6-one (Compound XIX) (XVI II )


ί ν ΐ

13. A method according to any one of the preceding claims wherein the compounds detected are detected and/or quantified using liquid chromatography or mass spectrometry or a combination thereof.

14. A method according to claim 13 wherein a compound is derivatised by reaction with a conjugation agent to facilitate detection.

15. A method according to claim 14 wherein the conjugation agent is a Girard agent.

16. A method of modulating Smoothened (Smo) receptor activity comprising administering to a patient in need thereof an amount of Compound VI or Compound XXL or pharmaceutically acceptable salt thereof.

17. A method of treating cancer comprising administering to a patient in need thereof an amount of Compound VI or Compound XXI, or pharmaceutically acceptable salt thereof.

18. The method according to claim 17 wherein the cancer is selected from the group consisting of an adenocarcinoma of the pancreas, prostate, breast, stomach, esophagus or biliary tract; a medullobiastoma or glioma; a small-cell lung cancer; a basal cell carcinoma; a rhabdomyosarcoma; a urothelial carcinoma; a squamous ceil carcinoma of the oral cavity; and a hepatocellular carcinoma.