Research reveals unexpected findings in the quest to repurpose a common cholesterol drug for a rare neurodevelopmental disorder
Imagine a neurological condition characterized by developmental delays, movement and balance problems, frequent seizures, and yet an unexpectedly happy demeanor with frequent laughter and smiling. This is Angelman syndrome (AS), a rare neurodevelopmental disorder that affects approximately 1 in 12,000 to 1 in 20,000 people 4 . For families and researchers alike, finding effective treatments has been a challenging journey marked by promising leads and disappointing dead ends.
A cholesterol-lowering medication showed potential for treating brain disorders in previous research, making it a promising candidate for Angelman syndrome.
Angelman syndrome results from the loss of functional expression of the UBE3A gene inherited from the mother 4 . This gene provides instructions for making a protein called ubiquitin protein ligase E3A, which plays a critical role in the normal function and development of the nervous system.
In most areas of the body, both the maternal and paternal copies of the UBE3A gene are active. However, in certain brain regions, normally only the maternal copy is active—the paternal copy is "silenced" through a process called genomic imprinting 3 . When the maternal copy is missing or mutated, those particular brain cells have no functional UBE3A protein, leading to the characteristic symptoms of Angelman syndrome.
Lovastatin belongs to a class of drugs called statins, primarily used to lower cholesterol. However, researchers had discovered that these drugs might have additional benefits for brain disorders. Previous studies had shown that lovastatin could reduce hyperexcitability and seizure susceptibility in another Angelman syndrome model 3 . The drug works by inhibiting the ERK signaling pathway, which is involved in cell growth and survival and appears disrupted in Angelman syndrome 1 .
The appeal of repurposing an existing, approved drug was significant. Lovastatin was already known to be safe and well-tolerated, approved for use in children, immediately available, and low-cost 3 .
The study employed a maternal deletion mouse model of Angelman syndrome that reliably reproduces many behavioral features relevant to the human condition 3 . These mice exhibit motor coordination deficits, gait abnormalities, and cognitive impairments—making them an ideal system for testing potential therapeutics.
The researchers designed a tailored set of behavior assays translationally relevant to Angelman syndrome, focusing specifically on motor function and simple cognition 3 . Their objectives were threefold:
B6.129S7-Ube3a maternal deletion mice from Jackson Laboratory 3
Acute dosing to both AS model mice and wildtype littermates
Conducted in order from least to most stressful with 48-hour intervals 3
Blinded assessment of genotype and treatment effects
| Test Name | What It Measures | Relevance to Angelman Syndrome |
|---|---|---|
| Open Field | Exploratory activity, locomotion, anxiety-like behavior | AS mice typically show reduced exploratory behavior (hypolocomotion) |
| Rotarod | Motor coordination, balance, and motor learning | Previously observed impairments in AS mice |
| Gait Analysis | Walking pattern, step length, width, and variability | AS involves gait ataxia and movement abnormalities |
| Novel Object Recognition | Simple learning and memory | Cognitive deficits are a core feature of AS |
| Overall Health and Sedation Monitoring | General well-being and potential adverse drug effects | Safety assessment of lovastatin treatment |
Contrary to what the researchers had anticipated based on previous studies, lovastatin failed to improve any of the core symptoms in the Angelman syndrome mouse model 1 . The results were consistently disappointing across all tested domains:
Perhaps most surprisingly, lovastatin administration caused deleterious sedative effects in the wildtype control mice and actually worsened their performance on the cognitive task 1 3 . This unexpected finding in healthy mice raised additional concerns about potential side effects.
| Resource Category | Specific Examples | Function in the Research |
|---|---|---|
| Mouse Model | B6.129S7-Ube3atm1Alb/J maternal deletion mice from Jackson Laboratory 3 | Recapitulate features of Angelman syndrome for therapeutic testing |
| Pharmacological Agent | Lovastatin | Experimental treatment targeting ERK signaling pathway |
| Behavioral Assessment Tools | Open field apparatus, rotarod, gait analysis system, novel object recognition setup | Quantify motor abilities, coordination, gait, and simple cognition |
| Genotyping Resources | REDExtract-N-Amp tissue PCR kit, specific primers for Ube3a gene mutation 3 | Confirm genotype of experimental animals (AS model vs. wildtype) |
| Animal Housing Equipment | Techniplast cages, controlled environment systems 3 | Maintain consistent environmental conditions throughout study |
| Ethical Oversight | IACUC approval, AAALAC accreditation 1 | Ensure humane and ethical treatment of research animals |
While negative results are often less celebrated than dramatic breakthroughs, they play a crucial role in advancing scientific knowledge. This lovastatin study prevents other researchers from pursuing similar dead ends and redirects valuable resources toward more promising approaches.
"Despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein" 3 .
The researchers acknowledged several limitations of their study. The acute, high-dose regimen they used might have produced different outcomes than chronic, lower-dose treatments more akin to how statins are used in humans 1 3 . Additionally, they focused exclusively on adult mice, leaving open the question of whether treatment during earlier developmental stages might be more effective.
Despite this setback, research for Angelman syndrome treatments continues to advance. Multiple promising approaches are currently being explored, including:
To reactivate the dormant paternal allele 2
Using viral vectors to deliver healthy UBE3A copies 3
The story of lovastatin in Angelman syndrome research serves as a powerful reminder that scientific progress is rarely linear. What appears to be a promising therapeutic candidate based on preliminary evidence may not withstand rigorous testing.
This research exemplifies the self-correcting nature of science, where hypotheses are continually tested, refined, or abandoned based on experimental evidence. For families affected by Angelman syndrome and the researchers dedicated to finding treatments, each result—whether positive or negative—helps to narrow the path toward effective interventions that will ultimately improve quality of life for individuals with this challenging condition.
As research continues to unravel the complexities of UBE3A function and brain development, each finding brings us closer to understanding not just Angelman syndrome, but the fundamental mechanisms of neurodevelopment that affect us all.