Cor­nell re­searchers to launch ear­ly tri­al of gene ther­a­py aimed — ul­ti­mate­ly — at pre­vent­ing Alzheimer's

The no­to­ri­ous dif­fi­cul­ty — if not im­pos­si­bil­i­ty — of re­vers­ing or slow­ing the pro­gres­sion of Alzheimer’s has pushed re­searchers to study much ear­li­er stages of the dis­ease, and the po­ten­tial of treat­ing pa­tients be­fore they show signs of brain dam­age. But can they go even ear­li­er than that — by tak­ing a pre­ven­tion ap­proach based on a ge­net­ic dri­ver of the dis­ease?

Ronald Crys­tal

Doc­tors at Weill Cor­nell Med­i­cine are giv­ing it a try with a gene ther­a­py de­signed to flood the brains of high-risk pa­tients with a low-risk ver­sion of the APOE gene, there­by knock­ing down their risk of get­ting Alzheimer’s to just av­er­age. In three months — pend­ing man­u­fac­tur­ing clear­ance — they will be­gin a 15-per­son tri­al to test if their in­fu­sion can in­deed lead to the right mix of genes (and sub­se­quent pro­duc­tion of pro­teins) in the brain.

Tar­get­ing the gene, prin­ci­pal in­ves­ti­ga­tor Ronald Crys­tal told MIT Tech Re­view, means his team doesn’t need to com­mit to any of the the­o­ries of what ac­tu­al­ly caus­es Alzheimer’s, whether it’s the dom­i­nant but in­creas­ing­ly shaky amy­loid-be­ta hy­poth­e­sis or the va­ri­ety of new tar­gets crop­ping up in re­cent years.

“What at­tracts us to Alzheimer’s is that the ge­net­ic epi­demi­ol­o­gy is so ob­vi­ous,” Crys­tal, a pro­fes­sor of ge­net­ic med­i­cine, said. “So the strat­e­gy is, can we bathe the brain in E2? We have the in­fra­struc­ture to do it, so we thought, why not? It gets around the prob­lem of the mech­a­nism of the dis­ease.”

By E2, he is re­fer­ring to the APOE2 gene, which is thought to low­er a per­son’s risk of de­vel­op­ing Alzheimer’s. For the tri­al, they are re­cruit­ing pa­tients with two copies of the APOE4 gene, the ver­sion of the apolipopro­tein E gene that por­tends the nasty mem­o­ry-wast­ing ail­ment. They will then in­ject bil­lions of virus­es con­tain­ing APOE2 to the pa­tients’ spinal cords.

Specif­i­cal­ly, Crys­tal told me, they are us­ing the AAV serotype rh.10 — a kind they have pre­vi­ous­ly ad­min­is­tered to chil­dren with Bat­ten dis­ease through di­rect in­fu­sion to the brain in a sep­a­rate tri­al. So while “you nev­er know un­til you do the stud­ies in hu­mans,” he is op­ti­mistic that safe­ty wouldn’t be a ma­jor con­cern.

Af­ter an­swer­ing the big ques­tions about safe­ty, the mea­sure of ef­fi­ca­cy will go as far as de­tect­ing the func­tion of the gene, since the ther­a­py is un­like­ly to al­ter the con­di­tions for a group of pa­tients al­ready di­ag­nosed with some form of cog­ni­tive im­pair­ment or de­men­tia due to Alzheimer’s.

“The con­cept is ra­tio­nal,” Crys­tal told MIT Tech Re­view. “Whether it works in a hu­man is an­oth­er thing.”

No­tably, on­ly about 2% of the world’s pop­u­la­tion are APOE4/4 ho­mozy­gotes, al­though one in four peo­ple car­ry a sin­gle copy, ac­cord­ing to the Ban­ner Alzheimer’s In­sti­tute.

Crys­tal ac­knowl­edged the small per­cent­age of po­ten­tial Alzheimer’s pa­tients with both copies of APOE4, but sug­gest­ed that E3/E4 het­erozy­gotes, who are al­so at risk (al­beit a small­er one) for the dis­ease, add to the pop­u­la­tion that the gene ther­a­py can ul­ti­mate­ly treat.

Nev­er­the­less, APOE4 is a well-known risk fac­tor that has been pop­ping up in Alzheimer’s news a num­ber of ways. Bio­gen and Ei­sai, to pick a re­cent ex­am­ple, were bashed hard when an­a­lysts found out they had pulled APOE4 car­ri­ers from a treat­ment arm of their big BAN2401 study, pos­si­bly skew­ing the re­sults in the drug’s fa­vor.

And then there’s Alzheon, whose plan to re­vive a once-failed drug by fo­cus­ing on a pop­u­la­tion of Alzheimer’s pa­tients with two copies of the APOE4 gene has been met with cold glares from pub­lic in­vestors.

Yet, be­cause the func­tion of the APOE gene re­mains some­what mys­te­ri­ous (there’s some ev­i­dence it’s as­so­ci­at­ed with amy­loid-be­ta de­po­si­tion), there have been few at­tempts to tin­ker with it di­rect­ly. One ex­cep­tion is the biotech start­up E-scape Bio, which has a plan to re­struc­ture APOE4 pro­teins in­to APOE3 — the “medi­um risk” type.

While both Voy­ager and J&J are al­so work­ing on gene ther­a­pies — most­ly still in pre­clin­i­cal stage — to com­bat Alzheimer’s, their fo­cus is on trig­ger­ing the pro­duc­tion of ther­a­peu­tic an­ti­bod­ies.

The al­most brute force ap­proach of Cyrstal’s up­com­ing study, then, makes it a some­what nov­el up­stream ap­proach aimed at pre­ven­tion.

The Alzheimer’s Drug Dis­cov­ery Foun­da­tion has com­mit­ted $3 mil­lion to the project, its largest grant to date ac­cord­ing to MIT Tech Re­view. It’s ex­pect­ed to wrap at the end of 2021.

John Hood [file photo]

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