Multigene profiling in the kidney to tailor drug therapy
OwnerSanjay Nigam, Satish Eralyinventors
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Abstract
Provided are compositions, transgenic animals and methods for screening and analyzing drugs for toxicity and clearance. Such methods include creating a transgenic animal that lacks expression of two or more slc22 family member—organic ion transporters. Further disclosed are methods useful in determining a subjects sensitivity and a drugs efficacy based upon single nucleotide length polymorphisms in organic ion transport genes.
Claims30
A double knockout non-human transgenic animal that lacks expression of at least two slc22 family member—organic ion transporters.
A non-human mammal that carries germline mutations in at least two slc22 family member—organic ion transport genes.
A method for determining whether a compound has toxic effects in humans, comprising administering the compound to an slc22 family member—organic ion transporter double knockout non-human mammal and evaluating any toxicity in the knockout non-human mammal.
A method of determine a drug treatment for a mammalian subject comprising:
- (i) identifying a polymorphism in an slc22 family member—organic ion transporter;
- (ii) determining if the polymorphism is associated with drug sensitivity using a knockin of an slc22 family member—organic ion transporter gene containing a polymorphism in a non-human transgenic animal;
- and
- (iii) identifying a drug that is efficacious for the subject based upon the polymorphism and any association with drug sensitivity based upon the polymorphism.
A substantially purified polypeptide selected from the group consisting of:
- (a) a polypeptide comprising SEQ ID NO:36;
- (b) a polypeptide encoded by a polynucleotide comprising SEQ ID NO:35;
- (c) a polypeptide comprising a sequence that is at least 80% identical to SEQ ID NO:36 and has OAT6 activity;
- (d) a polypeptide that is encoded by a polynucleotide that hybridizes to a nucleic acid consisting of SEQ ID NO:35 under moderate to high stringency conditions and wherein the polypeptide has OAT6 activity;
- and
- (e) a polypeptide comprising a fragment of any of (a) to (d) above having OAT6 activity.
An isolated polynucleotide selected from the group consisting of:
- (a) a polynucleotide comprising SEQ ID NO:35;
- (b) a polynucleotide that encodes a polypeptide having a sequence as set forth in SEQ ID NO:36;
- (c) a polynucleotide that hybridizes to the complement of a nucleic acid consisting of SEQ ID NO:35, under stringent conditions of 0.5 M NaHPO4, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1×SSC/0.1% SDS at 68° C. and encodes a functionally equivalent OAT6 polypeptide;
- (d) a polynucleotide that hybridizes to the complement of a nucleic acid consisting of SEQ ID NO:35, under moderately stringent conditions of washing in 0.2% SSC/0.2% SDS/0.1% SDS at 42° C. and encodes a functionally equivalent OAT6 polypeptide;
- and
- (e) a fragment of any of (a) to (d) that are at least 15 nucleotides in length.
A transgenic organism comprising a knockout of OAT6.
Dependencies are inferred from the claim text.