Researchers at Cold Spring Har­bor Lab­o­ra­to­ry (CSHL), work­ing in col­lab­o­ra­tion with DepYmed Inc., a CSHL spin­out com­pa­ny, today report that they have con­duct­ed promis­ing pre­clin­i­cal exper­i­ments on a com­pound that could be used to treat Wilson’s dis­ease and pos­si­bly oth­er dis­or­ders — includ­ing cer­tain types of can­cer — in which lev­els of cop­per in the body are ele­vat­ed, caus­ing or con­tribut­ing to pathol­o­gy.

Wilson’s dis­ease, affect­ing 1 in 30,000 peo­ple, is a severe inher­it­ed dis­or­der that leads to pro­found liv­er and neu­ro­log­i­cal dam­age. It is caused by muta­tions in a gene called ATP7B that encodes an enzyme crit­i­cal in the excre­tion of excess cop­per from cells and organs.

Cop­per, like many oth­er met­als, is obtained main­ly through the diet. Although essen­tial in bod­i­ly func­tion, it can be tox­ic when it accu­mu­lates. Nor­mal­ly, amounts of cop­per are pre­cise­ly reg­u­lat­ed both at the cel­lu­lar lev­el and in the body as a whole. In Wilson’s patients, abnor­mal cop­per buildup begins in the liv­er, the organ that col­lects the met­al from the gut and dis­trib­utes it to oth­er tis­sues via the blood­stream.

Cop­per tox­i­c­i­ty can lead to liv­er enlarge­ment, hepati­tis, cir­rho­sis and even liv­er fail­ure, neces­si­tat­ing a trans­plant. As the dis­ease pro­gress­es, it can also affect the brain, with symp­toms that include speech defects, cog­ni­tive impair­ment, psy­chi­atric dis­or­ders, tremors, dys­to­nia and Parkin­son­ian symp­toms. Although Wilson’s dis­ease can’t be con­trolled by switch­ing to a low-cop­per diet, it is often man­age­able with drugs when treat­ed ear­ly.

“Unfor­tu­nate­ly, Wilson’s dis­ease may be hard to diag­nose because its ear­ly symp­toms are shared by oth­er ail­ments, and so it is often not treat­ed prompt­ly” says CSHL Pro­fes­sor Nicholas Tonks, who, with Nava­sona Krish­nan, Ph.D., for­mer­ly of his lab, led the research. “More­over, cur­rent­ly used treat­ments, involv­ing ‘de-cop­per­ing’ agents, have side effects and late­ly have become very expen­sive.”

The team’s new research con­firms that DPM-1001, a small mol­e­cule, robust­ly reduces cop­per lev­els in cells grown in cul­ture that were sam­pled from Wilson’s dis­ease patients, as well as sys­tem­i­cal­ly in a mouse mod­el of Wilson’s dis­ease. It acts as a chela­tor — a com­pound that inter­acts with a met­al to facil­i­tate its nat­ur­al removal.

The team showed that DPM-1001 is oral­ly avail­able — it could be tak­en as a pill — and is “exquis­ite­ly spe­cif­ic” for cop­per. Cur­rent de-cop­per­ing agents tend to affect lev­els of oth­er met­als in addi­tion to cop­per — an unde­sir­able fea­ture in a drug for an ill­ness like Wilson’s. Such drugs would like­ly be tak­en for extend­ed times, and the bind­ing of met­als oth­er than cop­per may con­tribute to unwant­ed side effects.

In a mouse mod­el of Wilson’s dis­ease, DPM-1001 ame­lio­rat­ed asso­ci­at­ed liv­er com­pli­ca­tions includ­ing enlarged cell size, irreg­u­lar shape and arrange­ment in liv­er tis­sue. This was accom­pa­nied by dra­mat­ic low­er­ing of tis­sue cop­per lev­els and reduced dis­ease symp­toms.

“It is our hope that this com­pound may rep­re­sent the basis for an improved approach to Wilson’s Dis­ease,” Tonks said. Opti­miza­tion work on the com­pound con­tin­ues in his lab in col­lab­o­ra­tion with DepYmed Inc.

Sto­ry Source:

Mate­ri­als pro­vid­ed by Cold Spring Har­bor Lab­o­ra­to­ry. Orig­i­nal writ­ten by Peter Tarr. Note: Con­tent may be edit­ed for style and length.

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