Gene ther­apy halts fatal brain disease


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F or the first time, doc­tors have used gene ther­apy to stave off a fatal de­gen­er­a­tive brain disease, an achieve­ment that some ex­perts had thought im­pos­si­ble.

The key to mak­ing the ther­apy work? One of the medicine’s great­est vil­lains: HIV.

The pa­tients were chil­dren who had in­her­ited a mu­tated gene caus­ing a rare dis­or­der, adrenoleukodys­tro­phy, or ALD. Nerve cells in the brain die, and in a few short years, chil­dren lose the abil­ity to walk or talk.

They be­come un­able to eat with­out a feed­ing tube, to see, hear or think. They usu­ally die within five years of di­ag­no­sis.

First symp­toms

The disease strikes about one in 20,000 boys; symp­toms first oc­cur at an av­er­age age of 7. The only treat­ment is a bone­mar­row trans­plant — if a com­pat­i­ble donor can be found — or a trans­plant with cord blood, if it was saved at birth.

But such trans­plants are an oner­ous and dan­ger­ous ther­apy, with a mor­tal­ity rate as high as 20 per cent. Some who sur­vive are left with life­long dis­abil­i­ties.

Now a new study, pub­lished on­line in the New Eng­land Jour­nal of Medicine, in­di­cates that gene ther­apy can hold off ALD with­out side ef­fects, but only if it is be­gun when the only signs of de­te­ri­o­ra­tion are changes in brain scans.

The study in­volved 17 boys (the disease strikes males al­most ex­clu­sively), ages 4 to 13. All got gene ther­apy. Two years later, 15 were func­tion­ing nor­mally with­out ob­vi­ous symp­toms.

“To me, it seems to be work­ing,” said Dr Jim Wil­son, direc­tor of the gene ther­apy pro­gramme at the Univer­sity of Penn­syl­va­nia’s Perel­man School of Medicine, who was not in­volved in the new study.

One of the re­main­ing two boys died; his disease pro­gressed so rapidly that gene ther­apy could not stop it. The other with­drew from the study to have a bone-mar­row trans­plant. He died of com­pli­ca­tions from the pro­ce­dure.

New av­enues

The study opens new av­enues for us­ing gene ther­apy to treat brain dis­eases, said Dr Theodore Fried­mann, a gene ther­apy pi­o­neer at the Univer­sity of Cal­i­for­nia San Diego School of Medicine.

“Many think the cen­tral ner­vous sys­tem is in­tractable and un­ap­proach­able,” he said. This study proves them wrong.

The re­search be­gan with a de­ter­mined mother, Am­ber Salz­man, who was an ex­ec­u­tive with a PhD in math­e­mat­ics at Glax­oSmithK­line. In 2000, her nephew was di­ag­nosed with ALD, a disease she had heard of only in the movie, Lorenzo’s Oil. He was “this won­der­ful sweet bril­liant kid,” Salz­man said. “All of a sud­den he loses his abil­i­ties. He crum­bles in front of your eyes.”

She had her one-year-old son tested and found that he had the mu­tated gene, as did an­other nephew.

She looked into Lorenzo’s oil, a dif­fi­cult di­etary reg­i­men fea­tur­ing a spe­cially de­signed oil.

Statis­ti­cians at her com­pany told her stud­ies of it did not show any ef­fect.

Salz­man met with Dr Tachi Ya­mada, who was head of re­search and devel­op­ment at Glaxo. “I said, ‘It will be a few years be­fore the bomb goes off in my son and other nephew. What do we do?’”

Ya­mada told her that her best bet was gene ther­apy, but it had never been tried against

a disease like ALD. In­deed, gene ther­apy had re­cently fallen out of favour af­ter 18-year-old Jesse Gelsinger died dur­ing an ex­per­i­men­tal treat­ment. Then, in 2003, four of nine chil­dren who got gene ther­apy for an im­mun­od­e­fi­ciency disease devel­oped leukaemia.

Salz­man, with as­sis­tance from her sis­ter, Rachel, and from other sci­en­tists, was un­de­terred. She cor­ralled re­searchers world­wide, ask­ing why a dif­fer­ent sort of virus couldn’t be used to slip a good ALD gene into the boys’ cells.

For Paul Ro­jas of Dover Plains, New York, whose son was in the study, gene ther­apy has been a life­saver.

He never heard of the disease un­til his son Brandon, who was 7, started drool­ing, los­ing his abil­ity to con­cen­trate and list­ing to one side when he walked.

Shock di­ag­no­sis

The di­ag­no­sis was a shock. And since Brandon was show­ing symp­toms, it was too late for a bone-mar­row trans­plant.

Brandon’s doc­tors, Ro­jas said, sat across from him and his wife, Lil­iana, in a small con­fer­ence room and gave them the bad news: “This is a disease that has no cure.”

He had his 4-year-old, Brian, tested. He had the mu­tated gene, too.

The Ro­jases could not find a com­pat­i­ble donor for a bone­mar­row trans­plant. But then they learnt about the gene ther­apy trial and got Brian en­rolled. He is now 7, with no sign of the disease.

But his older brother Brandon, now 10, no longer speaks, walks or eats. He has a feed­ing tube.

“Brian misses play­ing with his brother,” Ro­jas said. “Brandon was his idol.”

For Salz­man, the re­sults of the new gene ther­apy study have come too late. She had to get treat­ment for her son be­fore he devel­oped symp­toms.

He had a cord blood trans­plant, which was suc­cess­ful. Her nephew also had one, but suf­fered com­pli­ca­tions and must use a wheelchair.

The re­sults of the new study also give rise to a con­cern that is be­com­ing a reg­u­lar fea­ture of gene ther­apy work and other new biotech ther­a­pies: How much will this treat­ment cost?

Blue­bird Bio is not say­ing — com­pa­nies gen­er­ally do not an­nounce prices un­til their drugs are ap­proved.

Dr David A. Wil­liams, chief sci­en­tific of­fi­cer at Bos­ton Chil­dren’s Hos­pi­tal and a prin­ci­pal in­ves­ti­ga­tor of the new study, ex­pects the price to be sim­i­lar to the hun­dreds of thou­sands of dol­lars it costs for a bone-mar­row trans­plant.


Lil­iana Ro­jas with her son Brandon in New York. Brandon was di­ag­nosed with ADL in Au­gust 2014. Now 10, he no longer speaks, walks or eats.

Top: Dr David Wil­liams vis­its the Ro­jas fam­ily (from left) ■ mother Lil­iana, son Brandon, fa­ther Paul and son Brian. Above: Brian, Paul and Brandon Ro­jas, at their home in Dover ■ Plains, New York.

A fam­ily photo shows Brandon Ro­jas at age 7, when he was ■ di­ag­nosed with ALD.

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