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Chemical found to reverse Down syndrome-like symptoms in mice

Sept. 4, 2013
Courtesy of Johns Hopkins Medicine
and World Science staff

Re­search­ers say they have found a com­pound that dra­mat­ic­ally bol­sters learn­ing and mem­o­ry when giv­en to mice with a Down syn­drome-like con­di­tion on the day of birth. 

The one-dose treat­ment seems to en­a­ble the cer­e­bel­lum, part of the brain, to grow to a nor­mal size, sci­en­tists wrote in the Sept. 4 is­sue of the jour­nal Sci­ence Transla­t­ional Med­i­cine

They cau­tioned that the drug has yet to be prov­en safe in peo­ple. Still, the find­ings hold prom­ise for de­vel­op­ing drugs like it, said the sci­en­tists, with Johns Hop­kins Uni­vers­ity School of Med­i­cine in Bal­ti­more and the Na­t­ional In­sti­tutes of Health. The com­pound is a small mol­e­cule of a type called “a son­ic hedge­hog path­way ag­o­nist,” mean­ing it bol­sters a spe­cif­ic pat­tern of chem­i­cal ac­ti­vity in cells.

“Most peo­ple with Down syn­drome have a cer­e­bel­lum that’s about 60 per­cent of the nor­mal size,” said re­search­er Rog­er Reeves of Johns Hop­kins. “We treated the Down syn­drome-like mice with a com­pound we thought might nor­malize the cer­e­bel­lum’s growth, and it worked beau­ti­ful­ly. What we did­n’t ex­pect were the ef­fects on learn­ing and mem­o­ry, which are gen­er­ally con­trolled by the hip­po­cam­pus [another brain struc­ture], not the cer­e­bel­lum.”

Down syn­drome oc­curs when peo­ple have three, rath­er than the usu­al two, cop­ies of chro­mo­some 21. As a re­sult, pa­tients have ex­tra cop­ies of the more than 300 genes housed on that chro­mo­some, which leads to in­tel­lec­tu­al dis­abil­i­ties, dis­tinc­tive fa­cial fea­tures and some­times heart prob­lems and oth­er health ef­fects. Since the con­di­tion in­volves so many genes, de­vel­op­ing treat­ments for it is a huge chal­lenge, Reeves said.

Reeves and his col­leagues used mice ge­net­ic­ally en­gi­neered to have ex­tra cop­ies of about half of the genes found on hu­man chro­mo­some 21. The mice have many char­ac­ter­is­tics si­m­i­lar to those of peo­ple with Down syn­drome, the re­search­ers said, in­clud­ing smaller cer­e­bel­lums and dif­fi­cul­ty learn­ing and re­mem­ber­ing how to nav­i­gate through a fa­mil­iar space.

Based on pre­vi­ous ex­pe­ri­ments on how Down syn­drome af­fects brain de­vel­op­ment, the re­search­ers tried su­per­charg­ing a bio­chem­i­cal chain of events known as the son­ic hedge­hog path­way that trig­gers growth and de­vel­op­ment. They used a com­pound that could do that, in­ject­ing it while the mouse cer­e­bel­lums were still de­vel­op­ing. “We were able to com­pletely nor­malize growth of the cer­e­bel­lum through adult­hood with that sin­gle in­jec­tion,” Reeves said.

The re­search­ers al­so looked for changes in be­hav­ior. “Mak­ing the an­i­mals, syn­the­siz­ing the com­pound and guess­ing the right dose were so dif­fi­cult and time-con­sum­ing that we wanted to get as much da­ta out of the ex­pe­ri­ment as we could,” Reeves said. The team tested the treated mice against un­treated Down syn­drome-like mice and nor­mal mice in a va­ri­e­ty of ways, and found that the treated mice did just as well as the nor­mal ones on the wa­ter maze test.

Reeves said fur­ther re­search is needed to learn why ex­actly the treat­ment works.


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Researchers say they have found a compound that dramatically bolsters learning and memory when given to mice with a Down syndrome-like condition on the day of birth. The one-dose treatment seems to enable the cerebellum, part of the brain, to grow to a normal size, scientists wrote in the Sept. 4 issue of Science Translational Medicine. They cautioned that the drug has yet to be proven safe in people. Still, the findings hold promise for developing drugs like it, said the scientists, with Johns Hopkins University School of Medicine in Baltimore and the National Institutes of Health. The compound is a small molecule of a type called “a sonic hedgehog pathway agonist,” meaning it bolsters a specific pattern of chemical activity in cells. “Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” said researcher Roger Reeves of Johns Hopkins. “We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum’s growth, and it worked beautifully. What we didn’t expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum.” Down syndrome occurs when people have three, rather than the usual two, copies of chromosome 21. As a result, patients have extra copies of the more than 300 genes housed on that chromosome, which leads to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. Since the condition involves so many genes, developing treatments for it is a huge challenge, Reeves said. Reeves and his colleagues used mice genetically engineered to have extra copies of about half of the genes found on human chromosome 21. The mice have many characteristics similar to those of people with Down syndrome, the researchers said, including smaller cerebellums and difficulty learning and remembering how to navigate through a familiar space. Based on previous experiments on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development. They used a compound that could do that, injecting it while the mouse cerebellums were still developing. “We were able to completely normalize growth of the cerebellum through adulthood with that single injection,” Reeves said. The researchers also looked for changes in behavior. “Making the animals, synthesizing the compound and guessing the right dose were so difficult and time-consuming that we wanted to get as much data out of the experiment as we could,” Reeves said. The team tested the treated mice against untreated Down syndrome-like mice and normal mice in a variety of ways, and found that the treated mice did just as well as the normal ones on the water maze test. Reeves said further research is needed to learn why exactly the treatment works.