Compositions and methods for in utero delivery

Abstract

Compositions and methods for fetal or in utero delivery of active agents are provided. The compositions are most typically administered intravenously via the vitelline vein, umbilical vein, or directly into the amniotic cavity of a pregnant mother. Growth factors can be delivered to correct structural defects. Gene editing can be carried out utilizing a gene editing composition such as triplex-forming molecules, CRISPR, zinc finger nucleases, TALENS, or others. The methods can include administration of a gene modification potentiating agent such as stem cell factor (SCF), a CHK1 or ATR inhibitor, or a combination thereof. A particularly preferred gene editing composition is triplex-forming peptide nucleic acids (PNAs) substituted at the γ position for increased DNA binding affinity. Polymeric particle compositions for extracellular and intracellular delivery of the active agents are also provided.

1 . A method comprising administering in utero to an embryo or fetus, an effective amount of a composition comprising a therapeutic, prophylactic or diagnostic agent encapsulated, entrapped, complexed to or dispersed in particles to treat a disease or condition in the embryo or fetus. 
     
     
         2 . The method of  claim 1 , wherein the particles are selected from the group consisting of microparticles, nanoparticles, and mixtures thereof. 
     
     
         3 . The method of  claim 2 , wherein the particles are formed of a polymer, copolymer or polymer blend selected from the group consisting of poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactide-co-glycolide) (PLGA), polyesters, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates), poly(lactide-co-caprolactone), poly(beta-amino) esters (PBAEs) and poly(amine-co-ester) polymers (PACE). 
     
     
         4 . The method of  claim 2 , wherein the particles comprises polymer or copolymer selected from the group consisting of alginate, chitosan, and poly(HEMA). 
     
     
         5 . The method of  claim 1 , wherein the particles comprise nanoparticles and the agent is a gene editing composition that corrects a mutation in the genome of the fetus or embryo. 
     
     
         6 . The method of  claim 5 , wherein the nanoparticles comprise PLGA, a blend of PLGA and (PBAE), or PACE. 
     
     
         7 . The method of  claim 5 , wherein the gene editing composition comprises a peptide nucleic acid (PNA) tail clamp that enhances recombination of a donor oligonucleotide in the fetal or embryonic genome to correct the mutation relative to the donor oligonucleotide alone. 
     
     
         8 . The method of  claim 7 , wherein the gene editing composition further comprises the donor oligonucleotide. 
     
     
         9 . The method of  claim 7 , wherein the PNA tail clamp comprises at least one PNA oligomer. 
     
     
         10 . The method of  claim 9 , wherein the at least one PNA oligomer of the PNA tail clamp is a modified PNA oligomer comprising at least one modification at a gamma position of a backbone carbon. 
     
     
         11 . The method of  claim 9 , wherein the modified PNA oligomer comprises at least one miniPEG modification at a gamma position of a backbone carbon. 
     
     
         12 . The method of  claim 5  wherein the disease or condition is hemophilia, a hemoglobinopathy, cystic fibrosis, xeroderma pigmentosum, or a lysosomal storage disease. 
     
     
         13 . The method of  claim 5  wherein the disease or condition is beta-thalassemia or sickle cell disease. 
     
     
         14 . The method of  claim 1 , wherein the particles comprise microparticles and the active agent is a growth factor that treats a structural defect in the embryo or fetus. 
     
     
         15 . The method of  claim 14 , wherein the microparticles comprise alginate. 
     
     
         16 . The method of  claim 14 , wherein the growth factor is a basic fibroblast growth factor. 
     
     
         17 . The method of  claim 14  wherein the structural defect leads to muscular dystrophy, Type 2 diabetes, or spina bifida. 
     
     
         18 . The method of  claim 1 , wherein the composition is administered to a fetus. 
     
     
         19 . The method of  claim 1 , wherein the composition is administered by injection or infusion into the vitelline vein. 
     
     
         20 . The method of  claim 1 , wherein the composition is administered by intraamniotic sac injection. 
     
     
         21 . A composition comprising an effective amount of a composition comprising a therapeutic, prophylactic or diagnostic agent encapsulated, entrapped, complexed to or dispersed in particles to treat a disease or condition in an embryo or fetus and a pharmaceutically-acceptable carrier, wherein the composition is either formulated for infusion or injection into a vitelline artery or a vitelline vein or formulated for intraamniotic sac injection. 
     
     
         22 . The composition of  claim 21  comprising a plurality of nanoparticles and a pharmaceutically-acceptable carrier,
 wherein at least one nanoparticle of the plurality of nanoparticles comprises a gene editing composition comprising at least one peptide nucleic acid (PNA) oligomer modified at a gamma position of a backbone carbon (γPNA) oligomer, 
 wherein at least one nanoparticle of the plurality of nanoparticles comprises a donor oligonucleotide, 
 wherein the composition is either formulated for infusion or injection into a vitelline artery or a vitelline vein or formulated for intraamniotic sac injection.