MED­I­CAL FRONT

EQUUS - - Equus -

• Gene ther­apy for laminitis? • How horses ask for help • The best way to treat sand colic • A ques­tion about anes­the­sia

pre­cau­tions

Thanks to a re­search break­through at the Uni­ver­sity of Penn­syl­va­nia’s New Bolton Cen­ter, it may one day be pos­si­ble to treat laminitis us­ing gene ther­apy that tar­gets dam­aged cells within the hoof.

An often de­bil­i­tat­ing in­flam­ma­tion of the hoof’s sen­si­tive lam­i­nae, laminitis is no­to­ri­ously dif­fi­cult to treat. “The is­sue with laminitis is that the dam­aged tis­sue [the lamel­lae] is highly spe­cial­ized,” ex­plains Dean Richard­son, DVM. “The tricky thing is ef­fec­tively treat­ing this highly spe­cial­ized tis­sue when we re­ally are not en­tirely sure of what ‘tar­gets’ within that tis­sue need to be treated.”

Richard­son and his re­search team have been in­ves­ti­gat­ing the po­ten­tial for gene ther­apy tech­niques to fun­da­men­tally al­ter cells within the hoof. “Gene ther­apy in this sense means that you de­fine a gene that codes for a pro­tein that you be­lieve will be ther­a­peu­tic. That

Ref­er­ence: “De­liv­ery and eval­u­a­tion of re­com­bi­nant adeno-as­so­ci­ated vi­ral vec­tors in the equine dis­tal ex­trem­ity for the treat­ment of laminitis,” Equine Vet­eri­nary Jour­nal, Jan­uary 2017 gene is then in­serted into a virus," he ex­plains. "Viruses are built to do one thing -get their ge­netic ma­te­rial into a host cell. Once that ge­netic ma­te­rial is in the host cell, it makes the pro­teins coded for by the virus. In nat­u­ral vi­ral in­fec­tions, this means that the host cells man­u­fac­ture many copies of the virus it­self. In gene ther­apy, the

PROM­ISE: In the type of gene ther­apy that may one day be used to treat laminitis, a gene would be in­serted into the DNA of a virus, which would then be in­jected into the horse. The virus would en­ter the horse’s cells and cause them to pro­duce a pro­tein that treats the dis­ease. vi­ral vec­tors are ‘crip­pled,’ mean­ing they are in­ca­pable of repli­cat­ing them­selves, but they still have the ma­chin­ery to en­ter the host cell.”

Once a vi­ral vec­tor con­tain­ing the de­sired gene en­ters a host cell, it makes the host cell pro­duce the de­sired pro­tein, says Richard­son. “That pro­tein is ex­pressed lo­cally and (the­o­ret­i­cally) treats the dis­ease process.”

The re­searchers tested this tech­nique on seven healthy horses with no his­tory of laminitis, us­ing “marked” genes that could eas­ily be iden­ti­fied af­ter de­liv­ery by one of six dif­fer­ent vi­ral vec­tors. The vec­tors were in­jected into the hoof through the pal­mar dig­i­tal artery, which runs down the side of the pastern. A tech­nique called re­gional limb per­fu­sion was then used to en­sure that the virus---and the gene it de­liv­ered---stayed within the foot for 30 min­utes.

Seven to 21 days later, the re­searchers found that three of the vi­ral vec­tors had pen­e­trated cells through­out the hooves, in­clud­ing the lam­i­nae. These vec­tors were even more widely dis­persed when com­bined with a sur­fac­tant, a sub­stance that re­duces sur­face ten­sion of a liq­uid and in­creases its spread­ing and wet­ting prop­er­ties.

Learn­ing that vi­ral vec­tors can de­liver genes to hoof tis­sue is only a pre­lim­i­nary step in the com­plex process of cre­at­ing a gene ther­apy, says Richard­son. Next the re­searchers will work to de­ter­mine which genes can be ben­e­fi­cial. “This is the ul­ti­mate ques­tion,” he says.

“Right now we have used some can­di­date genes [specif­i­cally, tis­sue in­hibitor of met­al­lo­pro­teinase-3 (TIMP3)] but we don’t know which or even how many can­di­dates there may be be­cause no one has com­pletely de­fined the patho­genetic path­ways of laminitis.”

GENE THER­APY US­ING A VI­RAL VEC­TOR sen­si­tive lam­i­nae frog bars sole hoof wall vec­tor binds to cell mem­brane vi­ral DNA new gene vi­ral DNA mod­i­fied DNA in­jected into vi­ral vec­tor vec­tor is pack­aged in vesi­cle vi­ral vec­tor vesi­cle breaks down, re­leas­ing...

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