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As a teen, was a talented artist and diligent student. When she started struggling with her studies and dropping basic items like her pencil, she told her parents something was wrong. Eventually, at age 18, she was diagnosed with Lafora Disease, or LD, a rare neurodegenerative childhood dementia and epilepsy.

Now, at age 26, Anissa doesn’t draw anymore and receives full-time care from her family and nurses.

Chelsea’s Hope

Anissa Merriam, who suffers from Lafora disease, enjoys a bike ride outdoors on a utility trike, which offers extra stability for those with motility challenges.

“Cognitively, she is like a little girl,” Anissa’s mother Jenifer Merriam said in a Washington Post . “This is a disease where we watch them go backward.”

LD is a genetic neurodegenerative disease that typically manifests in adolescence. It is caused when the body cannot properly process the energy storage molecule glycogen due to mutations in the phosphatase EPM2A or E3 ubiquitin ligase EPM2B/NHLRC1. Patients with LD suffer from seizures, cognitive decline and loss of muscle coordination that worsen as the disease progresses. These symptoms are due to the buildup of insoluble glycogen aggregates that form in the brain, skin, heart, liver and other peripheral tissues.

LD is part of a larger family of diseases called glycogen storage diseases, or GSDs, which collectively affect 1 in 20,000 to 43,000 newborns annually.

For LD patients, including Anissa, there is no effective treatment or cure — care focuses around managing symptoms and providing support. From the time of their first seizure, most patients diagnosed with LD typically die within 10 years, or by age 30.

, professor and chair of biochemistry and molecular biology at the University of Florida, has been researching LD for over 20 years. He knows first-hand how impactful rare disease research can be to the patients and families impacted by these diseases — he has been collaborating with the patient community since his time as a postdoctoral fellow in the lab of former ɬÀï·¬ President Jack Dixon at the University of California, San Diego.

“The LD community got me hooked on studying the glycogen storage diseases and Lafora disease in particular,” Gentry said. The community now hosts annual workshops and supports both patient advocacy and research. 

Gentry’s work has been bolstered by this community throughout his career. He has maintained close connections with the LD advocacy group . The group — which was founded in honor of Chelsea Gerber, who was diagnosed with LD at 15 and succumbed to the disease at age 26 — helps connect families and promotes LD research. , a former graduate student in Gentry’s lab and now scientific and executive director for Chelsea’s Hope, said patients and their families are important partners in rare disease research.

“If you empower the patient community and (work hand in hand with them), they can really be huge supporters of the science, and they see the direct benefit to their community,” Donohue said.

By collaborating with the rare disease community, Gentry has contributed to the biochemical understanding of LD and developed three potential therapeutics for LD-related conditions. Yet, as with all rare diseases, many hurdles and unknowns remain, especially for patients like Anissa and their families, hoping for a cure.

Bong Riola, Chelsea’s Hope

Kit Donohue, scientific director at Chelsea’s Hope, speaks to the audience during the 2024 Lafora Disease Science Symposium in San Diego, CA.

Common themes, shared treatments

Since starting his lab in 2014, Gentry’s research has expanded from LD to also include other GSDs, leading to a better picture of the disease biochemistry.

“We rolled out this idea that there are about six different diseases that we could (call) neurological GSDs,” Gentry said. “For five of the six, the centerpiece is the idea that glycogen needs to be downregulated or degraded in order to treat patients.”

These six diseases include LD, , Cori’s disease (also known as and .

Since the grouping of these diseases, Gentry said GSD researchers are focused on finding therapeutics that prevent or degrade the disease-causing glycogen aggregates, known as Lafora bodies. Because five of these diseases share a common mechanism, a single drug could be effective. In addition to having a more patient impact, this approach helps address some of the challenges associated with developing rare disease therapeutics, including cost.

Gentry said rare diseases often have complex biology and limited patient populations, making it difficult to identify and test new therapeutics. According to the , almost one in 10 people in the U.S. have a rare disease, but only about 5% of rare diseases have treatments approved by the U.S. Food & Drug Administration. 

“LD is so ultrarare that no company wants to take a treatment forward,” Gentry said. “This idea that one drug could now be used for five different diseases is a game changer in terms of the finances that companies are willing to look at.”

So far, Gentry and others have developed multiple to treat neurological glycogen storage diseases that are currently in preclinical and clinical development. Gentry and colleagues are targeting GSDs from three different biochemical angles: degrading existing glycogen aggregates using an antibody–enzyme fusion, downregulating glycogen synthesis using an antisense oligonucleotide, and inhibiting the glycogen synthase enzyme using a .

M. Kathryn Brewer, University of Florida

Scanning electron micrograph of a Lafora body, an insoluble glygogen aggregate, that can form in the brain, heart, skin and other peripheral tissues of patients with Lafora disease.

Two of these therapeutics have already undergone successful early clinical trials. The antisense oligonucleotide, called ION283, targets the messenger RNA of a key enzyme in the glycogen synthesis pathway, glycogen synthase 1. with this therapeutic conducted by Donohue during her time in Gentry’s lab showed promise in an animal model, and a safety study with LD patients is underway.

Gentry has also collaborated with Valerion Therapeutics to develop an antibody-based system capable of delivering therapeutics directly into cells. This system takes advantage of an anti-DNA antibody, called 3E10, that is taken into cells through a nucleoside transporter. By fusing an enzyme capable of degrading glycogen to this antibody, this therapeutic can effectively reduce glycogen accumulation. One of this therapy has been investigated in early clinical trials for Pompe disease. Gentry’s lab has investigated another and, in a mouse model of LD, observed a significant reduction of Lafora bodies in the brain and other tissues.

Donohue said the collaboration between the patients and scientists has been a key driver of this therapeutic development. In fact, the patient community is for the antisense oligonucleotide.

“You need patients, scientists and clinicians collaborating on understanding what’s going to be not only the best from a basic science perspective, but what will be the best therapy for the patient,” Donohue said.

From rare to common

Beyond therapeutics, Gentry said that studying rare diseases provides insight into more common diseases as well as unaffected brain homeostasis.

“Rare diseases are nature’s mistakes so they can give us insight into how biology works,” he said. “The work we did on LD directly drove our understanding of a new mechanism in lung cancer, and that’s not something I would have necessarily expected.”

In a , Gentry and colleagues observed that glycogen metabolism is a key driver of lung adenocarcinoma, the most common lung cancer in the U.S. The team used spatial analysis of human lung adenocarcinoma samples and observed that glycogen accumulation was associated with more aggressive tumors and poorer survival. Using genetic models and dietary intervention, Gentry and colleagues also observed that increased glycogen levels were correlated with tumor progression.

A multiplexed spatial imaging technique developed by at the University of Florida, based on mass spectrometry imaging, further demonstrated the link between glycogen levels and metabolites essential for tumor growth, supporting the idea that glycogen accumulation drives cancer progression in lung adenocarcinoma. This biochemical understanding and link between glycogen accumulation and cancer progression could open the door for new treatments.  

Although his work has expanded beyond LD, Gentry said he still credits the success of rare disease research and the insights provided into more common diseases, to a key group — the patients and their families.

Matt Gentry

Matt Gentry, a professor and chair of biochemistry and molecular biology at the University of Florida, and collaborator Ramon Sun, associate professor at University of Florida department of biochemistry and molecular biology and director of the University of Florida Center for Advanced Spatial Biomolecule Research, discussing the results of a collaborative spatial imaging project.

Patients as partners

Gentry maintains close contact with patients suffering from the diseases he researches — he is a scientific advisor for advocacy groups for adult polyglucan body disease and GLUT1 deficiency syndrome and Both Gentry and Donohue have seen the active role patients and their families can play in advancing rare disease research.

“Through an advocacy organization, (the patients) become part of the conversation,” Donohue said. Researchers also benefit from these connections. “It gives them a better concrete vision of what their research is going towards and potential applications for their research that maybe they hadn't considered before,” Donohue said.

Chelsea’s Hope

Emine Malaj, who suffers from Lafora disease, poses for a photo outdoors.

Fatos Malaj, whose daughter was diagnosed with LD after she started suffering from seizures at age 10, reached out to Chelsea’s Hope after receiving Emine’s diagnosis. He said Chelsea’s Hope has become their “big family” that offers unlimited support and has even participated in the annual research symposiums.

“My participation in the (2023 Lafora Science) Symposium was a turning point for me,” Fatos said. “There I met family members with the same problems and doctors that I had never imagined meeting, even in my wildest dreams. My best experiences with the researchers were participating in both Symposiums."

Emine and Anissa’s families have helped advocate and fundraise for the safety trials for the LD therapeutics in development. Without any current treatment options, the LD therapeutics in development serve as a beacon of hope for these patients and their families.

When Merriam learned about the ongoing LD research, “I just sat and cried,” she said in a Washington Post . “I was given a death sentence for my daughter 10 years ago and sent home. They gave me hope that I will not have to bury my daughter.”

Although there is still plenty of work ahead, the patients, their families and the researchers can rely on the tight-knit collaborative community they have built to continue to push towards new insights and treatments.

“I think the rare disease community offers a unique avenue to help innovate in the world of science,” Donohue said. “We know the current development pipeline doesn’t work for us. But, if we can fix the system for us, it will benefit the entire community because you will have all of the nuts and bolts lined up to create treatments for everyone.”