Sharon Bradley got the jitters on the drive from Pearland to the hospital where her husband was scheduled to receive an experimental treatment never before tried in an ALS patient.

The couple hoped the immunotherapy would buy Larry time in his battle with amyotrophic lateral sclerosis (ALS), the terminal neurodegenerative disorder that traps patients in an increasingly paralyzed body. But they also knew something could go wrong in a new therapy only tested in mice, that it could hasten the disease's development rather than slow it.

One patient initially interested in the treatment got cold feet.

"Are you sure you're game?" Sharon asked.

"No matter what, we don't have a lot of time, " Larry, unperturbed, told his wife. "I want to try this for myself. But at the end of the day, if it doesn't make a difference for me, maybe it'll make a difference for someone else."

Researchers haven't had much luck devising treatment to make a difference in the lives of ALS patients, who on average die three to five years after diagnosis. Now Dr. Stanley Appel, a Houston Methodist Hospital doctor who's considered a world leader in the field, is hoping he's unlocked an answer.

Appel's approach, funded by an Ice Bucket Challenge grant, involves injecting patients with their own immune cells, cells that had become dysfunctional in the body but were normalized and expanded in the laboratory after their removal. The idea is that again functioning properly in the body, the cells will help prevent the deterioration that characterizes ALS.

If clinical trials confirm the approach works, Appel thinks it might provide chronic treatment, much like insulin for diabetics.

Lou Gehrig’s disease

ALS, also known as Lou Gehrig's disease, is one of medicine's most devastating disorders, an attack on nerve cells in the brain and spinal cord that control voluntary movement. The resulting muscle degeneration leaves patients unable to walk, talk, swallow and, ultimately, breathe.

"It's a ringside seat as the body wastes away," says Appel.

The disease afflicts about 30,000 people in the United States, two in every 100,000. Most die within three to five years.

About 15 percent of cases are linked to a mutation in one or more genes, but the disease's cause or causes are unknown in the rest. It can strike anytime — patients have been diagnosed as young as 18 and as old as 88 — but the average time of onset is the mid-50s.

Appel started the world's first multi-disciplinary ALS clinic in the 1980s, following the referral of one of former President Lyndon Johnson's right-hand people. Appel became so touched by the quality of patients he treated — he calls ALS "nice guy's disease" — that he pledged to stay in the game until there was treatment to offer. Now, at 85, he has no plans to stop.

Over the years, Appel and his team of researchers made key discoveries about the immune system's role in ALS. They were the first to observe patients and their families shared an unusually high number of immunological diseases, such as multiple sclerosis, systemic lupus and thyroid disease. Later, they showed the immune system doesn't cause ALS but is enlisted in the process when the motor neuron signals it to destroy the neuron when its injuries are beyond repair.

The big breakthrough came when Appel's team crossed an ALS mouse model with a mouse without an immune system, expecting the offspring to live longer because they were removing an actor integral to the disease process. Instead the mouse died earlier, a sign that part of the immune system was still playing a protective role.

It turned out the key missing cells were regulatory T cells, or T-regs, which protect the body from harmful inflammation that accelerates the progression of ALS. Appel saw a potential therapy.

‘A death sentence’

Bradley's symptoms started with a twitch. It was like one you'd see in someone's eye, except it was in his left and right arms and it never took a break. He initially didn't pay it much attention, but a few months later, when it was keeping him up at night and he'd begun losing weight, he made an appointment with his doctor.

He got the bad news a few weeks later, in June 2015, from a neurologist who said simply, "I'm sorry, but you have ALS."

Bradley said he began to sweat profusely. All he could think about was Sharon and how he was going to explain to his two sons that he'd been diagnosed with a fatal disease that had no cure.

"Being diagnosed was like receiving a death sentence without the possibility of parole," says Bradley, now 50. "I'll never forget the look on my wife's face."

Bradley spent that day crying and having "my pity party." The next day, he moved on. He figured he could sit around and feel sorry for himself or face the disease head on. A regional sales manager for an oil and gas company, he went back to work.

The Bradleys found their way to Appel soon after the diagnosis. They figured they had their guy when they sought out a second opinion at Johns Hopkins and the doctor there mentioned that Appel was his mentor.

Appel told the Bradleys he was putting together a clinical trial for which Larry could be a candidate, given he was still in the early stages of the disease, when the T-reg dysfunction is still moderate. There were no guarantees — the Phase 1 trial was small and mostly designed to establish the therapy was safe — but the experimental therapy might slow the progression of his ALS.

In January 2016, Bradley received the first infusion of T-reg cells, about 100 million, a 30 percent to 40 percent increase on the amount in his body. He went home to wait on the results.

‘Outside the box’

It would be hard to overstate the need for new ALS therapy. There are currently only two approved treatments — one drug, Rilutek, approved by the Food and Drug Administration in 1995, which extends life by a couple months; and a new drug, Radicava, the FDA approved last year after a six-month trial in Japan found less of a decline in daily functioning in those who got it than those who didn't. There is no data yet on whether Radicava prolongs survival.

Other researchers in the field were initially skeptical of Appel's approach, arguing that any benefit from an infusion of normalized T-reg cells likely wouldn't last long because the problem was the environment. Back in the ALS patient, it'd be only a matter of time before the cells reverted to a dysfunctional state, they figured.

Such skepticism is nothing new to Appel, who'd been told his thinking was too far outside the box when he proposed 20 years ago that neuro-inflammation was a cause of ALS, not just an effect.

"The box is empty," Appel, since vindicated, told them. "That's why I'm outside the box."

Appel took an unconventional path just to get to medicine. He was pursuing an MBA at Harvard when he realized he was more interested in the human brain and its enigmas. Not a great believer in psychoanalytic theory, the fashion of the day, he opted instead to become a neurologist. In 1977, he arrived in Houston, recruited by then Baylor College of Medicine President Michael E. DeBakey to head the school's neurology department.

A Boston native, he cuts a memorable figure, typically dressed in lab coat, boots and a bow tie. Despite his love of the Boston Red Sox, his office sports two large busts of Gehrig, the New York Yankees slugger who became the face of ALS after the disease ended his playing career in the late 1930s.

Appel considers the T-regs immunotherapy his great hope, the culmination of years of research. He's busy planning a Phase 2 trial, to be conducted at Methodist and Harvard and designed to test if the therapy works better than a placebo. If it does — the trial is scheduled to start this fall — he thinks that might be enough for FDA approval.

The bigger hurdles are still to come. Among the issues his team faces: Can researchers eventually get the annual cost of the therapy under $100,000, a likely threshold for insurance to cover? Can they make Will continued monthly infusions of T-reg cells work over the long haul?

‘A game changer’

The therapy worked great for Bradley, twice, like it did for the study's other two participants. He got infusions from January to June in 2016 and again from January to June 2017. Both times it stopped the progression of his ALS — no lost muscle strength in his legs, arms and hands, no lost breathing function — during the period he received the cell infusions and for a month to two later.

But during the hiatus and since the trial ended — there was no provision or funding to extend the therapy — Bradley's disease began progressing again. It is now too advanced for him to qualify for Appel's Phase 2 trial — or any other.

He's lost much of his function, including the ability to walk and talk, though he gets around in a $30,000 motorized wheelchair and communicates by virtue of computer software embedded with eye-tracking technology. By looking at a digital keyboard on the screen and staring at the desired letter or number, he is able to type his thoughts.

Sharon is trying to convinced Larry that they should still travel, particularly to Rome, long on their bucket list. Patients with advanced ALS, after all, have gone to places such as Machu Picchu and Alaska.

Still, both know they don't have forever. At Methodist's ALS clinic earlier this month, they began having the difficult discussion with Appel about what to do when he can no longer breathe on his own, whether he wants his windpipe to be fitted with a tube and let a machine do the breathing.

Bradley is philosophic about it all. By email, he acknowledges he wishes he could continue with the trial because it worked, but says he understands why he's no longer qualified and is ok with it.

"Phase 2 of the T-reg study is coming up and I'm excited for the individuals that will get to participate," says Bradley. "I truly think, based on my personal experience, that T-reg Infusions will be a game changer for all ALS patients in the future."

todd.ackerman@chron.com

twitter.com/chronmed