Diagnostic assay and treatment for preeclampsia
Described is a method of diagnosis or prognosis of preeclampsia in a pregnant subject, comprising providing a sample from a pregnant subject and measuring the ratio between the amount of (a) one or both of sFlt-1 and PlGF, and (b) one or both of a breakdown product of heme and a breakdown product of arginine, in the sample. Also described are assay kits and a computer adapted for use in the method. Also described is a method of treating preeclampsia, comprising administering a pharmaceutically effective amount of L-arginine and/or citrulline and an inhibitor of arginase or pharmaceutically acceptable salts thereof. Also described is a method of treating cancer, comprising treating a subject with a therapeutically effective amount of an anti-VEGF compound, L-arginine and an arginase inhibitor.
1. A kit comprising
(a) an assay for measuring PlGF, an assay for measuring sFlt-1, or an assay for measuring both PlGF and sFlt-1; and
(b) an assay for measuring one or more arginine breakdown products, an assay for measuring one or more heme breakdown products, or an assay for measuring both of one or more arginine breakdown products and one or more heme breakdown products; and
(c) instructions for calculating the ratio of measured PlGF or sFlt-1, or both, to the one or more breakdown products;
where each of said assays is configured to be used on a biological sample from a pregnant host animal; and where the instructions include a correlation between the ratio and the probability that the host animal has or is at risk of developing pre-eclampsia.
2. The kit of claim 1 wherein the one or more arginine breakdown products is selected from the group consisting of urea, ornithine, citrulline, arginosuccinic acid, and ammonia, and and combinations thereof.
3. The kit of claim 2 , wherein the arginine breakdown product is urea.
4. The kit of claim 1 wherein the one or more heme breakdown products is selected from the group consisting of bilirubin, biliverdin, carbon monoxide, ferritin, and biopyrrin, and combinations thereof.
5. The kit of claim 4 , wherein the heme breakdown product is bilirubin.
6. The kit of claim 1 wherein the assay is an immunoassay.
7. The kit of claim 1 wherein the instructions further include a method for treating pre-eclampsia in the pregnant host animal having at least a threshold ratio of measured PlGF or sFlt-1, or both, to the one or more breakdown products.
8. The kit of claim 7 wherein the one or more arginine breakdown products is selected from the group consisting of urea, ornithine, citrulline, arginosuccinic acid, and ammonia, and combinations thereof.
9. The kit of claim 7 wherein the one or more heme breakdown products is selected from the group consisting of bilirubin, biliverdin, carbon monoxide, ferritin, and biopyrrin, and combinations thereof.
10. A process for preparing (i) an assayable fraction of sFlt-1 or PIGF, or a combination thereof; and (ii) an assayable fraction of one or more breakdown products of heme, or one or more breakdown products of arginine, or both one or more heme and arginine breakdown products from a biological sample from a pregnant host animal; the process comprising:
(a) extracting a soluble fraction of (i) sFlt-1 or PIGF, or both, and (ii) one or more breakdown products from the biological sample;
(b) adding one or more sFlt-1-specific or PlGF-specific binding agents, or a combination thereof, to at least a portion of the soluble fraction; where said binding agents are configured to quantify at least a portion of the amount of sFlt-1 or PlGF, or both, in the fraction;
(c) adding one or more breakdown product specific binding agents to at least a portion of the soluble fraction; where said binding agents are configured to quantify at least a portion of the amount of the one or more breakdown products in the fraction.
11. The process of claim 10 wherein each of said assayable fractions is configured for use in the diagnosis of preeclampsia in a pregnant host animal.
12. A method for prophylactic treatment of preeclampsia in a host animal, the method comprising:
measuring sFlt-1 or PIGF, or a combination thereof in the host animal;
measuring one or more arginine breakdown products, one or more heme breakdown products, or both of one or more arginine breakdown products and one or more heme breakdown products in the host animal;
calculating the ratio of sFlt-1 or PIGF, or the combination, to the one or more breakdown products;
and modulating sFlt-1 activity, PIGF activity, arginine breakdown, or heme breakdown, or a combination thereof in the host animal.
13. The method of claim 12 wherein the preeclampsia is late onset preeclamsia.
14. The method of claim 12 wherein the preeclampsia is severe preeclamsia.
15. The method of claim 12 , wherein the one or more arginine breakdown products is selected from the group consisting of urea, ornithine, citrulline, arginosuccinic acid, and ammonia, and combinations thereof.
16. A method for treating severe preeclampsia in a host animal, the method comprising measuring sFlt-1 or PIGF, or a combination thereof, in the host animal; measuring one or more arginine breakdown products, one or more heme breakdown products, or a combination of one or more arginine breakdown products and one or more heme breakdown products in the host animal; calculating the ratio of sFlt-1 or PIGF, or the combination, to the one or more breakdown products; and modulating sFlt-1 activity, PIGF activity, arginine breakdown, or heme breakdown, or a combination thereof in the host animal.
17. The method of claim 16 , wherein the one or more arginine breakdown products is selected from the group consisting of urea, ornithine, citrulline, arginosuccinic acid, and ammonia, and combinations thereof.