In certain situations, and for certain people, Nanci Ryder still hasn't lost her ability to smile. But in the six years since she was diagnosed with amyotrophic lateral sclerosis (ALS), Ryder has lost almost everything else, including the ability to walk, speak, sit up unaided, and feed herself. For a time, she was able to share her characteristic wit and feisty spirit by tapping out messages on an iPad preprogrammed with some of her famously salty turns of phrase or holding up little signs that a friend had custom-made for her saying things like "Shoe shopping, please" or "I can hear, I just can't speak."

By late 2019, however, Ryder no longer could make any voluntary movements. Her sole means of communication was fixing her gaze on one of two signs put up on the wall of her home: "Yes" or "No." "Even that takes time now. It's increasingly difficult," says Oscar-winning actress Renee Zellweger, a former longtime client of Ryder's and one of her closest friends. "We go slowly, and if she doesn't respond to something, we move on."

But in rare moments, Ryder, 67, can still smile. At a recent photo shoot at her Los Angeles home—the kind of gathering she once presided over with style and skill—Ryder lit up with obvious delight when Zellweger and Friends star Courteney Cox (also a former client of Ryder's) entered the room and flopped down on the couch to gossip with her as they always have. "When you get one of Nanci's smiles, nothing feels better in the world," Zellweger says. But she also knows when Ryder is angry. "There's a look in her eye; if I've been away too long for work, I know I'm being punished. But as soon as I let her know how bad I've been, she'll smile."

For many people with ALS, a progressive and incurable degenerative neuromuscular disorder, the first symptoms are muscle weakness or cramping, tripping, and dropping things. But for Ryder, it was her voice. At first it was an unusual hoarseness, even though she didn't have a cold. Then her speech became slow and slurred. "Everyone who was close to her noticed that something had changed with her speech," says Cox.

For seven months, Ryder went from specialist to specialist—a gastroenterologist; a speech pathologist; an ear, nose, and throat doctor; a dentist; a neurologist—in search of an explanation. Finally, in August 2014, Ryder got a diagnosis. As she sat with Zellweger in the office of Merit E. Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston, she was told she had a bulbar-onset form of ALS, which means the muscles of the head and neck are affected first, leading to difficulties with speaking and swallowing.

Over time, Dr. Cudkowicz explained, the nerve cells that control voluntary movement would deteriorate and die, and Ryder would gradually lose her ability to eat, speak, move, and breathe. Dr. Cudkowicz couldn't say how long Ryder would live other than to tell her that most people with ALS live between two and five years after diagnosis, although some survive up to 10 years and beyond.

"I recorded everything Dr. Cudkowicz said on my phone," says Zellweger. "I wasn't sure it was sinking in. It was too overwhelming." Afterward, the two women went for a walk around Boston. "I remember Nanci asked directions of a woman who was passing by, and she was already slurring a little. The look on that lady's face—it was judgmental. Her presumption about Nanci's condition was that she'd had a martini lunch or something. It hit me, 'Oh, this is really going to be something going forward.'"

Both Ryder and Zellweger realized ALS would be an entirely different ordeal from the one Ryder had faced in 2000, when she was diagnosed with breast cancer. "When she got that diagnosis, I was in England finishing up the original Bridget Jones movie, and she called me there to tell me. She started the treatments when I got home, and I would take her to the hospital," Zellweger says. "With breast cancer, she knew what to do and she knew she had a chance. After the ALS diagnosis, she said to me once, 'Cancer was easy.'"

A New Focus

Somehow Ryder found the strength to face this new threat. She was determined to raise funds and awareness for a disease that, at the time, had only one treatment, riluzole (Rilutek), which was approved in 1995 by the US Food and Drug Administration to slow the progression of ALS and prolong patients' survival. Another drug, edaravone (Radicava), was approved in 2017. The benefits of these two drugs are limited: Rilutek extends life expectancy by about three to five months, and Radicava's improvements—a slower decline on a scale that measures the ability to perform certain tasks like climbing stairs—were found only in a small subgroup of patients. But multiple new treatments are in the pipeline, and Ryder has made it her life's purpose to advocate for more research.

After decades working behind the scenes, expertly guiding TV and magazine interviews for her celebrity clients, the deeply private Ryder put herself in front of the cameras, doing interviews with outlets like The Hollywood Reporter and the syndicated program The Doctors to raise awareness about ALS, for as long as she was able to speak.

"With breast cancer, Nanci knew there was community outreach and knowledge about the disease," says one of her doctors, Robert H. Baloh, MD, PhD, FAAN, director of neuromuscular medicine at Cedars-Sinai Medical Center in Los Angeles. "She wanted to bring that level of attention to ALS and drive funding for patient care and research, and she was willing to tell her story in a very candid way. I remember having discussions with her early on, saying, 'Are you really sure you want to do this? It's not easy.' A lot of times people are encouraged to become advocates because of who they are or who they know, and they take on not only having a very challenging disease but having to go to events and put themselves out there. But Nanci never flinched. 'No, that's what I want to do,' she said."

To help her, a cadre of famous friends—including Cox, Zellweger, Michael J. Fox, Reese Witherspoon, Sarah Michelle Gellar, and one of her oldest and dearest friends, Don Diamont, star of The Bold and the Beautiful ("She saves her biggest smiles for Don," says Zellweger)—formed "Team Nanci" and have become a powerful presence every year at the ALS Association Golden West Chapter's Los Angeles County Walk to Defeat ALS, raising more than $750,000 so far.

"I would do anything for Nanci. It makes me feel a little less helpless," says Cox. "I can show up and hope that by my showing up, she knows I love her. If there's one extra person who finds out about this disease, I'm doing something. But it's not enough."

Ryder has no immediate relatives, but the "family" that sustains her through the worst of her disease includes Zellweger, Cox, Witherspoon, and Kathy Shawver Maffei, a close friend who has become one of Ryder's regular caregivers, in addition to her 24-hour nurses, twins Jerome and Jerald Cowan.

"We spent many weekends together where she would cry, and I would just hold her," says Cox. "We'd get our nails done together. She'd come over and walk our yard. As things progressed, she'd come in her wheelchair. I brought a stationary bike to her house because we wanted to help her keep up her muscles."

"When Nanci was first diagnosed, I didn't know anything about ALS beyond the name," says Zellweger, who thanked Ryder in her Best Actress acceptance speech when she won the Academy Award for Judy in February. "I didn't know that a body could do that—that it could just stop working, one piece at a time, and give no warning about what's next. We all educated ourselves and discussed the road ahead. It was not just essential but inevitable. The conversation has been ongoing and daily, and as changes surface there are more questions, and we go to Dr. Cudkowicz and Dr. Baloh for help."

Great Memories

But Cox and Zellweger also mourn what they've lost. "We used to go to lunch on Thursdays at Cecconi's, an Italian restaurant in West Hollywood, and just sit there and talk for hours," Cox says. "Nanci was always a great conversationalist, but she's also a great listener. I'd tell her everything that was going on in my life, and I knew she'd never judge me. She loved me unconditionally. Nothing made me happier than meeting Nanci for lunch."

Zellweger recalls trips with Ryder to fashion shows in France. "I can see her perched on her big white bed in her white bathrobe with her glasses, going through all the magazines because she had to see if her clients had to respond to anything, and ordering cookies, just in her bliss," she says. "Or we'd be backstage at an awards show and she'd be helping me into and out of a dress that's like origami with 55 different hidden enclosures, playing a game of Twister in these teeny tiny spaces."

Those adventures are over. "Her days are limited now, as her disease is progressing," says Shawver Maffei. "We have to pick and choose what we can and cannot do based on how she's feeling. It's very important to keep her as healthy as possible, so we have a strict rule in the house that if you have even a stuffy nose, stay out. She still goes to events, but in bustling settings she can't stay long."

On a typical day, the Cowans will wake Ryder up, wash and dress her, and take her downstairs. She gets regular massages from a nurse or massage therapist to ease pain, improve blood circulation, and reduce stiffness. "When the weather is bad, she'll sit by a fire in her den and watch TV, never missing The Bold and the Beautiful," says Shawver Maffei. During warm weather, Ryder will sit for hours in her backyard watching the trees and the sky with her two dogs and three cats. She doesn't need help with breathing yet, but her food and medications are delivered through a feeding tube. In the later stages of ALS as the muscles needed to breathe weaken, patients rely on artificial ventilation, which ranges from a tracheostomy or ventilator to the non-invasive bilevel positive airway pressure (BiPAP) machine.

Friends hope Ryder may yet benefit from one of the new ALS drugs in development, but for various reasons she's been ineligible for all the current trials. That hasn't defeated her. "She's determined to educate people about ALS, raise money, and find a cure," says Shawver Maffei.

When Zellweger comes to visit, sometimes she'll just climb into bed with Ryder, and they'll watch the news together. "I'll fill her in on everything that's happening and watch for signs of interest. If something is boring, I'll change subjects," Zellweger says. "The outings are fewer and further between, but we still send invitations [to Ryder] because we want her to know that we'd like her to be there."

Ryder is passionate about animals and became a member of the Safari Society at the Los Angeles Zoo shortly before her diagnosis. Her friends still occasionally take her for behind-the-scenes tours at the zoo. "Kathy and I will hop in the cart with Nanci, and it's just a peaceful, happy day, seeing the new baby seals or springboks or elephants or whatever it might be. It brings her a lot of joy," Zellweger says.

Watching Ryder's disease progress has been frightening, says Zellweger. "You're not born knowing how to manage something like this with grace. Every time I see her, I don't know what to expect in terms of how she'll be or how my own emotions will be," she says. "But like any friendship, it has stages and evolves. You adapt. You trust that the love you feel will help you navigate. You just show up. I have accepted that this is how I will go forward in our friendship. I will continue to love her, to advocate for her, and to show up."

Ryder is often sad and frustrated, Shawver Maffei admits. "But Nanci's also grateful for the love and support from her friends. It's truly amazing. Some days are wonderful, and some days are not so good, but we take the good and bad and make it work the best we can."

The Status of ALS Research

It's been almost six years since the "Ice Bucket Challenge" went viral and raised more than $115 million for amyotrophic lateral sclerosis (ALS) research in just eight weeks. Since Hollywood publicist Nanci Ryder was diagnosed with ALS in 2014, her posse of famous friends, dubbed "Team Nanci," have raised $750,000 for research. That influx of money has energized the field. Multiple genes linked to this neurodegenerative disease have now been identified, including two that are the most commonly known genetic causes.

"We are at an unparalleled time in ALS research, for a variety of reasons," says Merit E. Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston. "The pace is much faster, and we have much more insight into the targets for both the sporadic [without a clear known cause] and genetic forms of the disease. There are 140-plus companies developing treatments, and the number of scientists in the field has probably tripled in the last decade—neurobiologists, engineers, and clinical researchers."

One of those researchers is Justin Ichida, PhD, endowed professor of stem cell biology and regenerative medicine at the University of Southern California (USC), who is studying the genetic underpinnings of ALS—with help from Ryder.

"She was kind and generous enough to come to USC to give a blood sample, and from that we were able to manipulate her blood cells to make motor nerve cells, the cells that degenerate in ALS," he says. "When we make cells in the lab, they degenerate more rapidly than a normal person's nerve cells. That allows us to understand what makes these motor neurons die and test new treatments on them. So far, very few approved drugs have any effect on these cells." People with ALS lose the ability to speak, eat, move, and breathe as their motor nerve cells die.

To pool the vast amounts of data generated by Dr. Ichida and other experts in the field and develop new treatments more quickly, the Sean M. Healey Center is leading a platform trial in conjunction with Tackle ALS, a fundraising website established by Tim Green, a former NFL player who has ALS. Traditionally, clinical trials evaluate one drug at a time and take months or years to start and conduct. In a platform trial, multiple drugs are tested at the same time using specialized tools, and new drugs can be added as they become available. The ALS platform trial officially launched in September 2019 with five experimental treatments.

"It's one infrastructure that continuously tests multiple drugs and pools control groups," says Dr. Cudkowicz, the platform trial's lead investigator. "At the end of 12 months you have answers for about 10 drugs instead of one. This wouldn't have made sense even two years ago because the pipeline wasn't there."

Besides the platform trial, five other drugs are in late-stage clinical trials. AMX0035, from Amylyx Pharmaceuticals, combines two agents that target different pathways linked to the death of nerve cells. Researchers expect to present results from its 132-patient trial—which has been funded by the ALS Association—later this year.

Tofersen, from Biogen, targets the superoxide dismutase 1 (SOD1) gene mutation associated with about 2 to 5 percent of all ALS cases. Early results were presented at last year's Annual Meeting of the American Academy of Neurology, and the study is now in phase 3.

NurOwn is a stem cell therapy, developed by BrainStorm, that induces cells from patients' own bone marrow to produce neurotrophic factors—which support the growth, survival, and differentiation of developing and mature neurons. In phase 2 results reported in Neurology in December 2019, a preselected group of patients with rapidly progressing ALS saw their disease stabilize for up to 12 to 16 weeks. The phase 3 trial has enrolled 261 participants and is expected to end this fall.

Arimoclomol, from the biotech company Orphazyme, takes aim at protein misfolding in motor neurons. When proteins misfold, they clump together and cause cell death. In laboratory tests, cells treated with arimoclomol produced a protective protein that inhibited clumping. The 76-week phase 3 trial is fully enrolled, and results are expected in early 2021.

Levosimendan, made by Orion, increases calcium sensitivity in both heart and muscle fibers and is already approved in almost 60 countries (although not the United States) to treat acute heart failure. A phase 3 clinical trial is evaluating its potential to preserve lung function in patients with ALS and delay the need for a ventilator. In a phase 2 trial, patients taking levosimendan experienced no significant improvement in lung function while seated compared with the placebo group. However, researchers found some improvement in lung function when patients were lying down. Seventy-one percent of participants reported side effects, including headache, falls, swallowing problems, and respiratory failure.

"We've never had so many trials at one time," says Dr. Cudkowicz. "When someone like Nanci Ryder and her friends are out there raising funds and increasing awareness, they're steering philanthropic dollars to the most innovative trials and attracting promising new researchers to the field. I think we're really on the verge of having multiple drugs for ALS. Maybe it's different drugs for different groups of people or at different stages of the disease, but I strongly believe we're almost there."

ALS Resources

• ALS Foundation for Life: alsfoundation.org; 508-655-4381
• ALS Therapy Development Institute: als.net; 617-441-7200
• Les Turner ALS Foundation: lesturnerals.org; 847-679-3311
• Muscular Dystrophy Association: mda.org; 800-572-1717
• National Institutes of Health ALS: ninds.nih.gov
• Navigating Life with ALS: BrainandLife.org/Books
• Project ALS: projectals.org; 212-420-7382 or 855-900-2ALS
• The ALS Association: alsa.org; 202-407-8580