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NeuroEpigenetics Lab Clears Path for ALS Breakthrough

In This Article

  • Scientists in Dr. Sadri-Vakili's NeuroEpigenetics Laboratory at Massachusetts General Hospital use postmortem tissue to identify what causes ALS and corroborate findings in patients
  • Investigators are exploring the role of inflammation in disease development and progression in hopes of translating this research into potential ALS treatments
  • Research findings put into question the use of HDAC inhibitors and their potential as a therapy
  • Mass General Healey Center's ALS Platform trial is accelerating the pace of early-phase ALS trials by allowing the assessment of several drugs in parallel

Scientists in the Healey Center for ALS and the NeuroEpigenetics Laboratory at the MassGeneral Institute for Neurodegenerative Disease are working to hasten the development of needed therapeutic interventions for amyotrophic lateral sclerosis (ALS). Currently, there are only two FDA-approved ALS treatments and both only modestly affect the disease course.

"Given the lack of drugs for neurodegenerative disease, a two-way conversation is needed between scientists and clinicians in order to bring effective treatments into the clinic for patients," says the lab's Principal Investigator Ghazaleh Sadri-Vakili, MS, PhD.

Dr. Sadri-Vakili, in partnership with the Athinoula A. Martinos Center for Biomedical Imaging at Mass General, has been key in accelerating the pace of discovery about ALS by combining basic lab research and clinical observation of patients with the disease.

"It's important for scientists working on the disease to pair up with clinicians and vice versa," she says.

Inflammation's Role in the Onset of ALS

Genetic mutations cause 10% of ALS cases. The remainder are sporadic. Utilizing postmortem tissue from the motor cortex (the brain area affected in ALS) and spinal cord, Dr. Sadri-Vakili and her team seek to understand what causes the majority of ALS cases. "There are several targets we're interested in, including inflammation," says Dr. Sadri-Vakili. "We know that there's an inflammatory phenotype in ALS. There's an increase in microgliosis and astrogliosis, and the glial cells in the brain or spinal cord are activated and release different proinflammatory chemicals, such as cytokines and chemokines."

"Having access to human samples is huge," says Dr. Sadri-Vakili. "It makes no sense to only use cellular and animal models that don't always recapitulate what's happening in patients. Using the data the clinicians are gathering, including biofluids and PET imaging, helps us begin to put together a picture of what could go awry. We use the postmortem data to confirm if what we're seeing in patients is what might exacerbate their disease."

These efforts continue to yield evidence that inflammation has a role in the progression of ALS—even if it might not be a cause. Dr. Sadri-Vakili has found altered markers of inflammation in the brain and spinal cord of patients. Key regulators of inflammation are also changed in the blood and cerebral spinal fluid of patients.

"All of this builds up a case that going after this inflammatory process and getting it under control could allow the neurons to survive longer. Then perhaps we could delay the onset of disease and slow its progression," she says.

Exploring Cromolyn Sodium's Efficacy in ALS

With so much evidence that inflammation is a factor in ALS, finding anti-inflammatory therapies is critical. Cromolyn sodium is an FDA-approved anti-inflammatory drug that clinicians use to treat asthma. Previously, Mass General researchers have shown that cromolyn controls the inflammatory response in an Alzheimer's disease mouse model.

Now, Dr. Sadri-Vakili's lab has done the same with their SOD1G93A mouse model of ALS. One phenotypic characteristic of these mice is that they lose their spinal cord motor neurons like patients do. ALS patients also become paralyzed because of denervation of the neuromuscular junction, where the nerves hit the muscle and regulate their contraction and movement.

Treatment with cromolyn resulted in a delay in disease onset in these mice.

"It actually spared the spinal cord motor neurons," says Dr. Sadri-Vakili. "We found that cromolyn treatment also decreased the denervation at the neuromuscular junction. More importantly, it had an effect on mast cells, one of cromolyn's targets, which cause more inflammation around the muscles. We saw a decrease in them and in the chemokines and cytokines in the spinal cord and the blood."

Studying HDAC Inhibition in ALS

Dr. Sadri-Vakili's behind-the-scenes ALS research is also contributing to researchers' knowledge about what doesn't work against ALS. For example, previous research suggested that enzymes called histone deacetylase (HDAC) inhibitors have therapeutic effects for neurodegenerative disease. ALS mouse models also showed that HDAC inhibitors are altered in the disease, indicating that they could be protective.

Dr. Sadri-Vakili did not believe enough background work had been conducted to definitively prove that HDACs are dysregulated in ALS. Her team found that HDAC levels weren't changed in ALS human postmortem brain and spinal cord tissue. Concomitant studies with their clinical colleagues at the Healey Center for ALS and PET imaging partners at the Martinos Center confirmed these findings. There was no change when the researchers bound a radiotracer (developed by the Martinos Center; called Martinostat) to the same classes of HDAC enzymes that were measured biochemically in the postmortem tissue.

"This type of study is critical," says Dr. Sadri-Vakili. "We are getting a better picture of some of these things that seem like a good idea to go after but actually might not be."

She continues, "When you're working on a disease, it's just as important to have real negative findings that you can learn from. We've just begun to scratch the surface with this."

Assessing ALS Drugs in Parallel at the Healey Center

Dr. Sadri-Vakili is most excited about Mass General's HEALEY ALS Platform trial led by Merit Cudkowicz, MD, MSc, and Sabrina Paganoni, MD, PhD. Platform trials allow researchers to assess the therapeutic efficacy of several drugs in parallel and sequentially. The HEALEY ALS Platform trial is transforming how ALS trials are conducted: the trial includes several statistical innovations including the use of one shared placebo group to measure the effects of several drugs. This means fewer participants will be assigned to placebo.

"When you have a fatal disease like ALS, it is critical to design studies that give clear answers fast, while also maximizing the chance for participants to receive active study medication" says Dr. Sadri-Vakili. "Setting up platform trials allows more patients to have access to one of several new experimental treatments. It's also allowed the field to build up this infrastructure so that every time you want to do a clinical trial, you don't have to start everything from scratch. It makes it a lot easier to recruit patients, get the drugs to them a lot faster and decrease the duration of the trial.

"What makes me most excited is knowing that if I find something in my lab, I have a path forward into the clinic," she says. "If I was anywhere else but Mass General, it would be really difficult to do that."

Visit the Sean M. Healey & AMG Center for ALS

Learn more about the Mass General Institute for Neurodegenerative Disease


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