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Her Mentor Developed ALS. Now Sabrina Paganoni, MD, PhD, Is Testing a Drug to Slow Its Progression


Sabrina Paganoni, MD, PhD, is embarking on a phase 2 trial of urate elevation in amyotrophic lateral sclerosis (ALS) with the drug inosine, building on earlier work done in Parkinson's disease. The recipient of a Clinician-Scientist Development Three-year Award in ALS Research discusses the mentors that have helped shaped her career and research on ALS.

BOSTON—Soon after beginning her residency in physiatry at Spaulding Rehabilitation Hospital here in 2007, Sabrina Paganoni, MD, PhD, was taken under the wing of Lisa Krivickas, MD, a specialist in the study and treatment of amyotrophic lateral sclerosis (ALS).

“I was very interested in her clinical work and research, and she was kind enough to mentor me,” said Dr. Paganoni, who had left her native Italy after finishing her medical studies at the University of Milan Medical School to get her doctorate in neuroscience at Northwestern University before completing her residency in Boston.

Unbeknownst to Dr. Paganoni when they first met, Dr. Krivickas had just been diagnosed with ALS. “She was soon using a cane, but she kept mentoring me,” Dr. Paganoni said. “Then she had to use a scooter, but she kept mentoring me.”

On September 22, 2009, at the age of 45, Dr. Krivickas died.

“I was very moved by Lisa's mentorship and guidance,” Dr. Paganoni said. “She died before I finished my residency. She wanted me to continue her work, and it's been my honor to do so.”

And so it's been her honor, she said, to work with other mentors who have shaped her research in ALS, including Merit Cudkowicz, MD, and Michael A. Schwarzschild, MD, PhD.

During her residency, Dr. Paganoni began working at the Massachusetts General Hospital (MGH) with Dr. Cudkowicz, director of the ALS Program and now also chief of neurology at MGH and professor of neurology at Harvard Medical School.

“Meeting Dr. Cudkowicz was a turning point in my career and an extraordinary opportunity to learn about ALS clinical research and trials.”

Together, they analyzed clinical trial databases and found that people with ALS who had high urate (uric acid) levels lived longer. They published their results in the Journal of Neurology in 2012.

In April, Dr. Paganoni, now assistant professor of physical medicine and rehabilitation at Harvard Medical School, received the Clinician-Scientist Development Three-year Award in ALS Research, cosponsored by the AAN and the ALS Association, for a phase 2 trial of urate elevation in ALS with the drug inosine (SURE-ALS2).

The trial builds on research into inosine and its urate-elevating effect pioneered by Dr. Schwarzschild, professor of neurology at Harvard Medical School.

Following preclinical work showing that higher levels of urate, a naturally occurring antioxidant, were associated with slower progression of Parkinson's disease (PD), Dr. Schwarzschild led the Safety or Urate Elevation in PD (SURE-PD) study. Results published in JAMA Neurology in 2014 showed that urate levels could be safely raised in PD with the drug inosine; a phase 3 trial testing urate for PD is now underway.

Dr. Paganoni is collaborating with Dr. Schwarzschild and other scientists including Gazaleh Sadri-Vakili, PhD, also at MGH, and Evangelos Kiskinis, PhD, at Northwestern University, on preclinical testing of urate elevation in the superoxide dismutase 1 mouse model of ALS.


DR. SABRINA PAGNANONI: “Increased levels of urate are associated with a higher risk of kidney stones and gout. We have to make sure its safe, that its taken in a reasonable way. There are many supplements reported to have benefits. Its important that we study them scientifically.”

By collaborating with Dr. Schwarzschild, Dr. Paganoni could quickly translate results obtained in the lab and in PD to ALS clinical trials. She has completed a pilot clinical trial to see if urate levels could be safely raised in ALS patients.

The Salah Foundation provided enough funding for Dr. Paganoni to conduct the initial pilot trial of inosine in 25 ALS patients. (The referral for funding had come from an ALS patient she was treating at MGH.)

The study showed that inosine was safe, tolerable, and effective in raising serum urate levels. The experience gained in this pilot trial formed the basis for the SURE-ALS2 trial, which she is now planning to get underway as soon as possible.

“In ALS, time is not on our side,” she said. “Our patients decline fast, and there is a lot of variability from patient to patient. So we need large numbers, in the hundreds, to really demonstrate efficacy. But we are taking this first step in a smaller group of patients. Hopefully that will be a stepping stone to a phase 3 study.”

Although inosine is available as a dietary supplement, Dr. Paganoni said that few patients are trying it on their own. “Increased levels of urate are associated with a higher risk of kidney stones and gout,” she said. “We have to make sure it's safe, that it's taken in a reasonable way. There are many supplements reported to have benefits. It's important that we study them scientifically.”

Even if the drug is shown to slow the progression of ALS, she said she doubts it would stop progression in its tracks.

“The hope for now is to slow its course,” Dr. Paganoni said. “Even if that doesn't seem exciting, it is still important. It can be seen as a building-block approach. Just as you need a cocktail of drugs in HIV or some forms of cancer to be effective, perhaps we can find a combination of compounds in ALS that will keep patients clinically stable.”


• Schwarzschild MA, Ascherio A, Beal MF, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: A randomized clinical trial JAMA Neurol 2014;71(2):141–150.
    • Paganoni S, Zhang M, Quiroz Zárate A, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis J Neurol 2012 259 (9): 1923–1928.