A fatal epileptic and glycogen storage disease, Lafora Disease rears its head during adolescence and steals a young person’s dreams for life.
Introduction
Lafora disease (LD) patients have a severe and rare form of epilepsy due to a glycogen storage disease. The first symptoms are often seizures or myoclonic jerks during late childhood or early adolescence. From then, patients experience a steady progressive decline in mental and physical abilities. There is no cure and LD is fatal within about a decade from onset. Groups from around the globe are working to better understand the molecular underpinnings of the disease and create animal models to inform and conduct preclinical studies. This collaborative community is hopeful that the next few years will bring their first targeted therapeutic to clinical trial.
Tell me about this rare disease
Genetic basis: LD is an autosomal recessive genetic disease. Two loss of function mutations in EMP2A or EMP2B (epilepsy, progressive myoclonus type 2A or 2B) cause the disease. Disease-causing documented mutations are nearly evenly split in these two genes [1].
EMP2A encodes laforin, a glycogen phosphatase and EMP2B encodes malin, an E3 ubiquitin-ligase. These two gene products interact to properly regulate glycogen storage in cells [2]. More recently, a third gene has been implicated in an early-onset, but slower progressive form of the disease- PRDM8. Its function remains unknown, but an LD-causative mutation leads to reduced cytoplasmic function of laforin and malin [3].
Without functional EMP2A and EMP2B gene products, cytoplasmic collections of glycogen form that are called Lafora or Polyglucagon bodies. These glycogen chains are normally degraded at a higher rate in neuronal cells, and their continued presence disrupts brain function.
Incidence: Estimated at 4 in 1 million.1 The encompassing, broader group of glycogen storage diseases, have an incidence of 1 in 20,000-43,000 [4].
Geographical locale of patients: Global. Some concentrations occur in Spain, Italy, France, Northern Africa, Southern India, Pakistan, and Middle Eastern countries with higher consanguinity [5].
Brief history:
1911: Lafora and Glueck publish the first paper describing glycogen inclusion bodies found in many tissues postmortem [6]
1998-2007: Basic research elucidates the biological functions of EPM2A and EPM2B and identifies their loss as causative for Lafora body accumulation and Lafora disease
2007: Chelsea’s Hope founded by parents of Chelsea Gerber as a LD patient advocacy, community, and fundraising group in North America
2016: A Program Project Grant from the NINDS is funded to bring together international efforts on LD to find a cure [7]
2019: The first clinical trial for LD, a natural history study, begins in the U.S. [8]
The state of the disease today: Patients receiving a LD diagnosis today have a terribly grim future of progressive mental and physical decline until death. An active and collaborative international set of researchers and clinicians is working to move top drug candidates to clinical trials. Glycogen synthase 1 (GYS1) is generally considered a good drug target for LD [2]. Although progress was significantly slowed by the COVID-19 pandemic, the hope is that the next decade sees an approved therapy, if not a cure, and a drug that could potentially help patients with other glycogen storage diseases.
What is it like to be a patient?
Who are the patients? Typically, Lafora disease patients are completely healthy throughout childhood. Then, as adolescents with no previous symptoms, they develop seizures, myoclonic jerks or learning disabilities in their pre-teen or early teen years. Depending on the patient’s mutations and other unknown factors, the disease moves at varying rates. Patients experience progressively more epileptic seizures and cognitive decline, eventually leading to aphasia, ataxia, and continuous seizing. These symptoms advance to a vegetative state and then death [5] [9]. These families are blindsided by the disease after enjoying a normal childhood together.
What do current treatment options look like? There are no curative treatments for Lafora disease. The only treatments are palliative and anti-seizure medications, although patients typically become refractory to anti-epileptic medications after a period [1].
Are there advocacy groups? In North America there is Chelsea’s Hope which has an active website and Facebook page. The only other group I found is called Lafora Initiative which has a Facebook page based out of Australia.
Are there genetic tests? A genetic test (whole exome or targeted sequencing) can be done to determine if a patient has a causative mutation in EPM2A or EPM2B. So far, approximately 100 mutations have been identified across the >200 families documented with the disease [10] [11]. Additionally, a neurologist can perform an EEG and/or MRI to examine brain function and determine if it is consistent with LD pathology. Skin biopsies have also been used to facilitate diagnosis, but are fraught with inaccuracies, so a genetic test is preferred.
How do researchers and clinicians study this disease? Are there any (good) model systems for drug development? Fortunately for the LD field, there are good mouse models readily available and characterized. Both laforin (Epm2a-/-)[12] and malin (Epm2b-/-)[13] knockout mice have been generated, are viable and develop Lafora bodies of glycogen, just as in the human disease. While these two models are generally accepted by the field, new mouse models are being generated as additional tools: a myc-tagged endogenous mouse malin (because of a lack of useful mouse malin antibodies); a mouse with a mutation based on a patient genotype (laforin-R240X knock-in); a malin knockout mouse with tamoxifen-inducible Gys1 deletion [14] [15]. A canine model also exists, and one group is developing a rat model. These are excellent tools for preclinical studies to assess the efficacy of drugs to modulate Lafora bodies in different tissues and especially the brain.
Are there natural history studies (in the past or on going)? Ionis Pharmaceuticals initiated the first natural history study as a clinical trial in the United States in 2019. As of October 2022, it is listed as completed, but no results are posted. A better understanding of the natural history, especially how it relates to underlying genetics, will inform drug development, and help match patients with the therapeutics most likely to work for their genotype.
Certain physicians or centers that are experts? Leaders in the field are part of a Project Program Grant (P01) from the NINDS. They include researchers and physicians in Spain, Canada and the United States (University of Kentucky, Indiana University, UT Southwestern and UC San Diego).
What are the major challenges for studying and curing Lafora? Money. Basic and preclinical research studies have shown promising results for multiple therapeutic candidates. Now the field needs (industry) partners who are willing to put in the money to support clinical trials.
The Cure Corner
What is needed for a cure? What does an ideal therapeutic look like? Mouse model studies suggest that, generally, earlier seems to be better in terms of intervention to slow or even possibly reverse accumulation of Lafora bodies [14]. The therapeutic must have sustained action or repeat administration to prevent any further progression of Lafora body accumulation for life. Since Lafora bodies in the brain drive pathophysiology, the drug must be active in the CNS. This means it either needs an intrathecal delivery or the ability to cross the blood brain barrier.
Are there companies already developing drugs? If so, what kind of molecules and what stage in development are they? There is limited industry participation and progress right now. Ionis Pharmaceuticals was going to move their GYS1 ASO into clinical trials but stopped due to company restraints. A similarly promising antibody-enzyme fusion drug ran into issues with the company backing it closing and its IP being in limbo. It has now been transferred to EnAble Therapeutics, but they provide no information regarding its status. Maze Therapeutics has a GYS1 inhibitor that is listed as soon to be in Phase 1 trials, but no information is available on it at ClinicalTrials.gov and industry experts expect it is likely a few years away from the clinic.
What are current therapies and treatments lacking? There are very limited treatments and therapeutics for LD patients. Initially, anti-epileptic drugs are used to treat the seizures, but before long the seizures become refractory to these interventions. Patients become wheelchair bound, are fed via G-tube and lose their ability to speak. In short, current options are thoroughly lacking and only minimally help in the short-term.
Could an RNA therapeutic fit the need? Yes, in fact RNA therapeutics are some of the leading options for LD patients.
Ionis’ ASO targeting GYS1 through an RNase H mechanism showed extensive pre-clinical success and the company identified a lead candidate to take into the clinic.
As mentioned, an ideal drug for LD must be effective in the brain. ASOs have been successful in intrathecal delivery [16]. While researchers are still understanding the critical cell types to target in the brain for LD, it seems that reducing LBs in multiple cell types in the brain (neurons as well as inflammatory cells) will produce the best therapeutic results.
Recently, an artificial miRNA targeting Gys1 demonstrated in vivo success at reducing Lafora bodies and neuroinflammation in a LD mouse model. The artificial miRNA was delivered through an AAV with the intention of a curative treatment rather than requiring multiple infusions throughout life [17]. This strategy requires more testing before taking into the clinic but is very promising due to its impressive level of neuronal Gys1 depletion (50%) and durable effect.2
While the ASO and amiRNA are the leading candidates for an RNA therapeutic for Lafora, gene therapy replacement through CRISPR or an AAV could theoretically cure LD. However, this would require individual patient genotyping and personalized medicine per genotype.
Active research has begun to develop a molecular understanding of the disease, but LD is unique to have a good target that is amenable to various therapeutic approaches. As such, the aforementioned non-RNA based therapeutics (antibody-enzyme conjugate and small molecule inhibitor) also offer hope for the LD community.
Conclusion
Like so many aspects of life, the Lafora disease community hit some speed bumps when the COVID-19 pandemic shocked the planet. Hopefully work will pick back up again for treatments for this devastating disease and the next few years will bring multiple drugs to the clinic. Importantly for a drug developer, a drug that targets glycogen synthase 1 could also be effective for other glycogen storage diseases.
Many thanks to Professor Matthew Gentry for his expertise, insight and comments on the Lafora disease field.
https://biochem.med.ufl.edu/profile/gentry-matt
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[12] Ganesh S, Delgado-Escueta AV, Sakamoto T, et al. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet. 2002;11(11):1251-1262. doi:10.1093/hmg/11.11.1251
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