Jeanne Lor­ing hadn’t stud­ied Parkin­son’s in 22 years when she got an email from a lo­cal neu­rol­o­gist.

The neu­rol­o­gist, Melis­sa Houser, didn’t know Lor­ing had ever pub­lished on the dis­ease. She was just look­ing for a stem cell re­searcher who might hear her out. 

“I think I was just picked out of a hat,” Lor­ing told End­points News. 

At a meet­ing in Lor­ing’s Scripps Re­search of­fice, Houser and a Parkin­son’s nurse prac­ti­tion­er, Sher­rie Gould, asked her why there was so much re­search done in stem cell trans­plants for oth­er neu­rode­gen­er­a­tive dis­eases but not Parkin­son’s. They want­ed to know if she would work on one. 

“Fund­ing,” Lor­ing told them, get me the fund­ing — $200,000 — and I’m yours.

That was in 2011. The decade that en­sued saw sci­en­tists on three con­ti­nents and both North Amer­i­can coasts work, some­times col­lab­o­ra­tive­ly, to use new tech­nol­o­gy to res­ur­rect a vi­sion once dis­card­ed for rea­sons that ex­tend­ed well be­yond sci­en­tif­ic. Now, re­searchers are close­ly watch­ing for the re­sults of the first such trans­plants in Japan while Bay­er-backed Blue­Rock is await­ing on­ly a fi­nal FDA go-ahead to start its tri­als. And af­ter near­ly 10 years of pa­tient and pub­lic-backed re­search, Lor­ing is to­day launch­ing her com­pa­ny, As­pen Neu­ro­science, from stealth mode with a tech­nol­o­gy oth­ers saw as un­work­able and an eye to­ward its own tri­als next year.

Some are even toy­ing around, cau­tious­ly, with the word “cure,” even as oth­ers – in­clud­ing the first doc­tor to ex­e­cute a trans­plant for Parkin­son’s – see more ex­cit­ing de­vel­op­ments else­where.    

“We’ve de­vel­oped symp­to­matic treat­ments,” Blue­Rock de­vel­op­ment VP Mike Scott told End­points.  “But with this re­gen­er­a­tive med­i­cine ap­proach, you’re talk­ing about re­vers­ing lost func­tion. It’s trans­for­ma­tive. It has the po­ten­tial to be a func­tion­al cure.”

As­pen en­ters with one of the most fa­mous names in stem cell re­search. Lor­ing did her PhD on stem cells be­fore most Amer­i­cans had heard of them and was dubbed by the late sci­ence jour­nal­ist Bradley Fikes, “a stem cell evan­ge­list” for her work over the en­su­ing decades. In 2001, she de­vel­oped 9 of the em­bry­on­ic cell lines George W. Bush ap­proved for re­search. 

“She’s one of the god­moth­ers of stem cell ther­a­py,” Scott said. 

Ear­ly promis­es

Lor­ing’s first at­tempt at ap­ply­ing her cell work in biotech came at Hana Bi­o­log­ics in 1987, where she tried to graft dopamine neu­rons in­to rats en­gi­neered with Parkin­son’s. Parkin­son’s symp­toms are caused by these dopamine neu­rons de­cay­ing — which af­fect not on­ly plea­sure, but al­so move­ment and body con­trol — and it had been the­o­rized that a trans­plant could curb or even re­verse the dis­ease. The long­stand­ing car­bidopa lev­odopal, or “L-dopa,” treat­ments sup­ple­ment the lost dopamine but can vary in their ef­fec­tive­ness and don’t re­verse the dam­age.

“There’s no turn­ing back,” Lor­ing said. “The on­ly way to turn back the clock is to re­place those neu­rons.”

The ex­per­i­ment proved promis­ing, but the com­pa­ny failed. Lor­ing pub­lished a pa­per and moved on­to Gen­Pham and Alzheimer’s mice. 

At the same time, Curt Freed and Robert Breeze at the Uni­ver­si­ty of Col­orado im­plant­ed a pa­tient for the first time with hu­man fe­tus-de­rived dopamine cells. From 1988 through 1999, they im­plant­ed 61 pa­tients and pub­lished re­sults show­ing some pa­tient im­prove­ment, but the ther­a­py went nowhere. The prob­lem, Freed said, had lit­tle to do with ef­fi­ca­cy. 

“It was al­most im­pos­si­ble to find the right kind of hu­man fe­tal tis­sue from abor­tion,” Freed, who is not af­fil­i­at­ed with As­pen or Blue­Rock, told End­points. 

The tech­nol­o­gy for an al­ter­na­tive emerged in 2006, when Shinya Ya­mana­ka demon­strat­ed how any liv­ing cell could be chem­i­cal­ly in­duced in­to stem cell state, ef­fec­tive­ly un­teth­er­ing stem cell re­search from its po­lit­i­cal and sourc­ing quan­daries. In 2011, Lorenz Stud­er, founder of the Memo­r­i­al Sloan Ket­ter­ing Cen­ter for Stem Cell Bi­ol­o­gy, pub­lished a Na­ture pa­per show­ing how dopamine neu­rons from these in­duced hu­man stem cells, al­so called in­duced-pluripo­tent stem cells (iPS), could be en­graft­ed on­to rats. Stud­er would go on to build that work in­to Blue­Rock in 2016. 

Lor­ing’s work lead­ing up to that 2011 meet­ing had large­ly been in ge­nomics — in­clud­ing found­ing Ar­cos Bio­sciences, the fore­run­ner of di­a­betes cell trans­plant Vi­a­cyte — and af­ter Gould and peo­ple with Parkin­sons’ raised the nec­es­sary lab funds through a sum­mit of Mt. Kil­i­man­jaro, she took a dif­fer­ent ap­proach than Stud­er and top re­searchers in Japan and Swe­den took. 

Whose cells?

Lor­ing sought to do an au­tol­o­gous as op­posed to an al­lo­gene­ic trans­plant:  Rather than take cells from an­oth­er hu­man, build up a large bank and then im­plant a cer­tain num­ber in­to a pa­tient, she want­ed to take a pa­tient’s own skin cells, turn them in­to stem cells and then dopamine neu­rons and fi­nal­ly im­plant them in­to the brain. 

“We’re the on­ly com­pa­ny do­ing au­tol­o­gous,” Kim Kam­dar, a No­var­tis al­umn and part­ner at Do­main As­so­ci­ates, which pro­vid­ed seed fund­ing, told End­points. “The beau­ty in a way is the per­son­al­ized med­i­cine.”

There were sci­en­tif­ic and eco­nom­ic rea­sons, though, that no oth­er com­pa­ny pur­sued that goal. They may be part of why Blue­Rock launched with $245 mil­lion from Ver­sant Ven­tures and Bay­er, while Lor­ing’s work was kept go­ing through pa­tient fund­ing and emerges now with $6.5 mil­lion in seed cash. (They are hop­ing to close on a Se­ries A in the first quar­ter of 2020.) 

Blue­Rock over years de­vel­oped bil­lions of cells they keep in cryo­genic stor­age in a New York lab. That costs mon­ey, as As­pen ex­ecs not­ed, but Freed and Scott sug­gest­ed that hav­ing to build a new cell line for each pa­tient would, like in­di­vid­u­al­ized CAR-T ther­a­pies, cost far more and in­tro­duced more po­ten­tial pro­duc­tion prob­lems.

“You would need to have a high­ly ro­bust, bul­let­proof, cell repli­ca­tion sys­tem,” Scott said.

Lor­ing says she’s de­vel­oped that. Lean­ing on her ge­nomics back­ground and a ma­chine learn­ing, she says she’s built tech­nol­o­gy to stan­dard­ize the process. She ar­gues that she can save mon­ey by man­u­fac­tur­ing far few­er cell lines.  

The plat­form will al­so al­low them to pre­dict and pre­vent mu­ta­tions in the cell lines, Lor­ing said, and be­cause the cells are from the pa­tient, their body will ac­cept them.

“We won’t have to im­muno­sup­press them,” she said.

Scott ac­knowl­edged As­pen’s im­muno­sup­pres­sion ben­e­fits. Blue­Rock plans to im­muno­sup­press pa­tients in its first clin­i­cal tri­al. But it’s not ac­tu­al­ly clear that pa­tients need the ubiq­ui­tous post-trans­plant drugs for a stem cell brain pro­ce­dure be­cause the im­mune sys­tem op­er­ates dif­fer­ent­ly be­yond the blood-brain bar­ri­er. Blue­Rock hopes to even­tu­al­ly stop giv­ing the drugs.

Freed gave im­muno­sup­pres­sants to every oth­er pa­tient ear­ly on, and then stopped giv­ing them en­tire­ly. His team has done 15 au­top­sies of for­mer pa­tients, he said, and not one showed a trans­plant wiped out by re­jec­tion.

“Our stud­ies have shown im­muno­sup­pres­sion is not re­quired,” Freed said.

The key ques­tion, though – will any of this be ef­fec­tive – may take a while to an­swer.

Does it work?

At the end of last year, re­searchers at Ky­oto Uni­ver­si­ty im­plant­ed the first of sev­en pa­tients with al­lo­gene­ic stem cells. Sci­en­tists are still ea­ger­ly wait­ing for the pro­ce­dure’s re­sults as it can take up to 6 or even 12 months be­fore the im­plant cells will ful­ly con­nect with the oth­ers and pa­tients be­gin to show re­sponse.

That de­lay, among oth­er is­sues, has some in the Parkin­son’s com­mu­ni­ty look­ing to­wards oth­er so­lu­tions. David Sulz­er, a neu­ro­bi­ol­o­gy pro­fes­sor at Co­lum­bia Uni­ver­si­ty who last year re­ceived a grant to help re­search the role of au­toim­mu­ni­ty in Parkin­son’s, said trans­plants have po­ten­tial – one day.

“It’s go­ing to need a lot of work,” Sulz­er told End­points, not­ing skep­ti­cism about cell lines and where cells will be in­sert­ed.

Among oth­er pos­si­ble ob­sta­cles is the fact that re­searchers don’t un­der­stand what caus­es Parkin­son’s at the deep­est lev­el.

It’s pos­si­ble, Scott said, that what­ev­er killed the first neu­rons will kill the new ones.

Freed for his part has moved on. He says most of his re­search on trans­plants showed they work es­sen­tial­ly the same as an l-dopa. It didn’t re­turn lost func­tion but pumped out dopamine at a steady pace, sav­ing pa­tients from hav­ing symp­toms os­cil­late through­out the day. He’s moved on to phenyl­bu­tyrate, a drug he thinks can halt the dis­ease. Oth­er re­searchers are work­ing on gene ther­a­pies.

The new­er trans­plants, though, promise im­prove­ments on Freed’s work and pa­tients backed it hop­ing for a sig­nif­i­cant rem­e­dy in their life­time. Af­ter the Kil­i­man­jaro fundrais­er for Lor­ing, Gould found­ed Sum­mit for Stem Cell to con­tin­ue back­ing her. Jen­nifer Raub, who has Parkin­son’s, lat­er be­came pres­i­dent, turned it in­to a 501c(3) and once raised over $1 mil­lion in a night to help find some­thing that had broad­er, more con­sis­tent and long-last­ing ef­fects than the l-dopa she was tak­ing.

“I made a con­scious choice, as many do, to seek an al­ter­na­tive to car­bidopa lev­odopa rather than wait un­til I can no longer func­tion,” she wrote to End­points

For Lor­ing, now in her 60s, As­pen rep­re­sents a unique op­por­tu­ni­ty. Her work has changed med­i­cine, but so far she’s di­rect­ly de­vel­oped no new FDA-ap­proved drugs. She hopes to be­gin test­ing a po­ten­tial one next year. They’ve al­ready be­gun find­ing pa­tients.

“It would be the cul­mi­na­tion of my ca­reer,” she said, “and I’ve in­vest­ed most of my life.”

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.