There has been sig­nif­i­cant in­vest­ment in the de­vel­op­ment of gene ther­a­pies for dis­eases caused by ge­net­ic mu­ta­tions – in most cas­es mono­genic, se­ri­ous dis­eases that af­fect small pa­tient pop­u­la­tions. Peo­ple liv­ing with these dis­or­ders, who pre­vi­ous­ly had few or no treat­ment op­tions, can great­ly ben­e­fit from these ad­vances. How­ev­er, many of these gene ther­a­pies cost mil­lions of dol­lars per pa­tient, mak­ing them eco­nom­i­cal­ly un­fea­si­ble for preva­lent dis­eases and rais­ing dif­fi­cult ques­tions about ac­ces­si­bil­i­ty, eq­ui­ty and sus­tain­abil­i­ty.

From the ear­li­est days of my ca­reer, I have be­lieved in the po­ten­tial of gene ther­a­pies to trans­form treat­ment, not just for ge­net­ic dis­or­ders, but al­so for preva­lent con­di­tions af­fect­ing mil­lions. At Paci­ra, we’re ex­plor­ing ex­act­ly that po­ten­tial with high-ca­pac­i­ty ade­n­ovirus (HCAd) vec­tors. This next-gen­er­a­tion de­liv­ery sys­tem could dra­mat­i­cal­ly ex­pand the reach of gene ther­a­py to treat non-ge­net­ic con­di­tions like os­teoarthri­tis, chron­ic back pain and oth­er mus­cu­loskele­tal dis­or­ders, of­fer­ing treat­ment op­tions to im­prove the health and qual­i­ty of life of mil­lions of pa­tients.

Tra­di­tion­al gene ther­a­pies have re­lied on ade­no-as­so­ci­at­ed virus (AAV) vec­tors, but AAVs come with lim­i­ta­tions such as lim­it­ed trans­gene car­go ca­pac­i­ty and low to medi­um trans­duc­tion ef­fi­cien­cy (cell pen­e­tra­tion) in sev­er­al tis­sues/or­gans re­sult­ing in the need for high dos­es that dri­ve up cost and safe­ty con­cerns. In con­trast, our HCAd vec­tor is much larg­er in size, with a di­am­e­ter of about 100 nanome­ters com­pared to around 20 nanome­ters for the AAV vec­tor. That means a sin­gle HCAd can trans­fer large genes and/or mul­ti­ple genes in a sin­gle vec­tor – up to 30,000 base pairs com­pared to AAV vec­tors’ far more lim­it­ed ca­pac­i­ty of be­tween 2,500 and 5,000 base pairs. This al­so en­ables HCAd to de­liv­er genes with longer DNA se­quences with­out hav­ing to split them up in­to mul­ti­ple vec­tors, as is the case in dual AAV ap­proach­es. Ad­di­tion­al­ly, HCAd vec­tors ex­hib­it high­er trans­duc­tion ef­fi­cien­cy, al­low­ing low­er dos­ing than AAV vec­tors in sev­er­al tis­sues and or­gans. Fur­ther­more, HCAd-de­liv­ered genes have a rapid on­set of gene ex­pres­sion of hours to days rather than days to weeks as ob­served with AAV. These at­trib­ut­es mean low­er pro­duc­tion costs, few­er side ef­fects and faster clin­i­cal ben­e­fit.

Op­ti­miz­ing HCAd vec­tors by cap­sid en­gi­neer­ing, how­ev­er, presents some chal­lenges. Giv­en its larg­er size and more com­plex struc­tures, mod­i­fy­ing cap­sid prop­er­ties is more dif­fi­cult than with an AAV vec­tor. We are ad­dress­ing this is­sue by em­ploy­ing pro­pri­etary AI-dri­ven cap­sid en­gi­neer­ing work­streams to en­able the op­ti­miza­tion of HCAd vec­tors.  Guid­ed by gen­er­a­tive AI mod­els, we are mod­i­fy­ing the sur­face of the vec­tor to in­crease its speci­fici­ty so it can en­ter tar­get cells even more ef­fi­cient­ly while low­er­ing en­try in­to non-tar­get cells. By in­creas­ing the vec­tor's speci­fici­ty and ef­fi­cien­cy, we can fur­ther de­crease the re­quired gene ther­a­py dose and re­duce po­ten­tial side ef­fects.

Un­til now, the fo­cus of gene ther­a­py has been to cor­rect de­fec­tive genes. At Paci­ra, we see the next wave of gene ther­a­pies fo­cus­ing on de­liv­er­ing genes en­cod­ing ther­a­peu­tic pro­teins that are pro­duced at the site of non-ge­net­ic dis­eases. Such treat­ments could ad­dress the un­met needs of large pa­tient pop­u­la­tions since many com­mon, chron­ic con­di­tions lack safe, ef­fec­tive and long-last­ing treat­ments. Giv­en the size of the af­fect­ed pop­u­la­tion, un­like cur­rent gene ther­a­pies for rare ge­net­ic dis­eases, these treat­ments should be priced sim­i­lar­ly to tra­di­tion­al drugs.

We are de­vel­op­ing PCRX-201, Paci­ra’s nov­el in­ves­ti­ga­tion­al gene ther­a­py for os­teoarthro­sis of the knee, and we have al­ready ini­ti­at­ed a Phase 2 study. Rather than treat­ing a mu­tat­ed gene, PCRX-201 us­es HCAd to es­tab­lish lo­cal (in the af­fect­ed knee), sus­tained pro­duc­tion of in­ter­leukin-1 re­cep­tor an­tag­o­nist (IL-1Ra) that blocks in­ter­leukin-1 path­way ac­ti­va­tion to re­duce chron­ic in­flam­ma­tion that leads to pain and loss of func­tion of the knee joint. Ad­di­tion­al­ly, in­hibit­ing the IL-1 path­way may have dis­ease-mod­i­fy­ing po­ten­tial as has been ob­served in pre­clin­i­cal stud­ies. PCRX-201’s unique de­sign trans­forms the joint in­to a “smart” ther­a­peu­tic fac­to­ry that churns out IL-1Ra on­ly when in­flam­ma­tion is ac­tive in the joint and is turned off once in­flam­ma­tion is quelled, of­fer­ing a self-reg­u­lat­ing, durable treat­ment with po­ten­tial to last years from a sin­gle in­jec­tion. Three-year ef­fi­ca­cy and safe­ty fol­low-up da­ta from our phase 1 study for PCRX-201 were pre­sent­ed this year in mul­ti­ple sci­en­tif­ic con­fer­ences in­clud­ing the Eu­ro­pean Al­liance of As­so­ci­a­tions for Rheuma­tol­ogy (EU­LAR) Con­gress, the Amer­i­can So­ci­ety of Gene & Cell Ther­a­py (AS­GCT) An­nu­al Meet­ing, and the Os­teoarthri­tis Re­search So­ci­ety In­ter­na­tion­al (OAR­SI) World Con­gress.

PCRX-201 may be just the be­gin­ning. This ap­proach has great po­ten­tial for treat­ing oth­er os­teoarthrit­ic joints and ad­di­tion­al mus­cu­loskele­tal con­di­tions, such as low back pain caused by in­ter­ver­te­bral disc de­gen­er­a­tion, as well as dis­eases be­yond the mus­cu­loskele­tal sys­tem. There­fore, we are cur­rent­ly ex­plor­ing HCAd gene ther­a­py ap­proach­es for a num­ber of tis­sues and or­gans that are af­fect­ed by com­mon, chron­ic dis­eases with high un­met med­ical needs.

Paci­ra’s HCAd plat­form is pi­o­neer­ing the evo­lu­tion of the gene ther­a­py land­scape — from treat­ments for rare ge­net­ic dis­or­ders to broad­er ap­pli­ca­tions in com­mon, non-ge­net­ic con­di­tions. Its greater DNA-car­ry­ing ca­pac­i­ty, ef­fi­cient cell pen­e­tra­tion and lo­cal­ized de­liv­ery may en­able tar­get­ed treat­ments to have sub­stan­tial clin­i­cal ben­e­fits while at the same time be­ing eco­nom­i­cal­ly vi­able to pro­duce and ac­ces­si­ble to pa­tients.

If suc­cess­ful, this ap­proach could fi­nal­ly move gene ther­a­py from aca­d­e­m­ic cen­ters and spe­cial­ty clin­ics in­to rou­tine clin­i­cal prac­tice, an evo­lu­tion that’s long over­due.