Bryostatin-1 in Long-term Use Seen to Arrest Fragile X Symptoms in Mouse Model

Long-term, but not short-term, treatment with bryostatin-1 — Neurotrope’s lead investigational therapy — arrested such behavioral and cognitive symptoms as hyperactivity, difficulties with daily life activities, and learning and memory deficits in a mouse model of fragile X syndrome.

These long-term effects are distinct from those seen with other experimental treatments for fragile X, which promote a phenomenon called tolerance: strong short-term benefits that fade with long-term use.

These findings add to previous reports of bryostatin-1 benefits on learning and memory in young and adult mice engineered to mimic fragile X manifestations, and support Neurotrope’s efforts to evaluate the therapy in people with the condition.

The study, “Chronic bryostatin-1 rescues autistic and cognitive phenotypes in the fragile X mice,” was published in the journal Scientific Reports.

Fragile X, the most common single genetic cause of autism spectrum disorder (ASD), can lead to cognitive impairment, learning disabilities, attention deficits, hyperactive behavior, seizures, and autism features that affect communication and social interaction.

It is caused by low-to-no levels of the fragile X mental retardation protein (FMRP), due to mutations in the FMR1 gene.

Highly present in the brain, FMRP regulates the production of several other proteins, many of which are essential for the development and maturation of synapses — the junction where nerve cells communicate.

Bryostatin-1, a small molecule that can cross the blood-brain barrier, works by activating protein kinase C, an enzyme required for maintaining synapse health, and involved in learning and memory. The blood-brain barrier prevents potentially harmful molecules in the circulating blood from reaching the brain.

In animal models of fragile X, Alzheimer’s disease, stroke, and other neurological disorders, the therapy promoted synaptic health and improved spatial learning and memory.

Notably, spatial learning and memory refer to the acquisition and memorization of a mental representation of the environment, allowing an organism to navigate in it and remember where things are. Both spatial and non-spatial learning and memory are highly dependent on the hippocampus, a brain region known to be affected in several neurological conditions, including fragile X.

Researchers at FRAXA Research Foundation, FRAXA Drug Validation Initiative and Neurotrope joined with collaborators in Chile and the U.K. to evaluate whether bryostatin-1 is also beneficial in autistic and other behaviors, as well as in non-spatial learning and memory, in a mouse model of fragile X.

This team measured changes in several behavioral and memory tasks following treatment with bryostatin-1 over five weeks (short-term; comparable to “many months” of use in humans) and 13 weeks (long-term; comparable to “years” of use in humans).

The therapy was given directly into the bloodstream twice a week at a dose of 20 micrograms per square meter. Selected tasks assessed hyperactivity and hippocampal-dependent daily living activities (nesting and marble burying), as well as non-spatial learning and memory.

Mice given short-term bryostatin-1 treatment had very limited to no behavioral and memory improvements compared with untreated mice, results showed. Longer treatment, however, significantly reduced hyperactivity, improved non-spatial learning and memory, and normalized daily living activities in these mice.

These findings highlighted that long-term, but not short-term, treatment “effectively rescued the autistic and non-spatial learning deficit cognitive [features],” the researchers wrote.

Long-term use of bryostatin-1 also resulted in no signs of tolerance, in contrast with other therapy classes tested to date in fragile X models, including mGluR5 antagonists, GABA-A receptor agonists, and GABA-B receptor agonists, the investigators said.

They added that this bryostatin-1 dose was previously shown to also lessen depressive behavior in rodents, a symptom associated with autism.

“It is possible the mechanism of the delayed therapeutic effect could be similar to anti-depressants that act pharmacologically in days but only therapeutically after 4–6 weeks,” the researchers wrote, and that “longer-term treatment would result in further improvement.”

Given the current lack “of specific and effective therapeutics for ASD and FXS [fragile X syndrome], bryostatin-1, with its therapeutic effects on cognitive impairment, hyperactivity, and depression, might have unique therapeutic values for ASD and FXS at its effective dose,” the team added.

These findings, including 13 weeks in mice amounting to years of treatment for people, may also help inform future clinical trials in fragile X patients, the scientists noted.

Neurotrope announced plans in 2018 to launch a pilot clinical trial evaluating bryostatin-1’s safety, tolerability, and preliminary effectiveness in children and adolescents, ages 8 to 17, with fragile X. No further details, including a possible date for the study’s start, have been provided.

Bryostatin-1’s long-term effectiveness is currently being evaluated in a Phase 2 trial (NCT04538066) in Alzheimer’s patients, after promising cognitive effects in preclinical studies. The company has also been developing  bryostatin-1 as a potential treatment for stroke, traumatic brain injury, and Niemann-Pick type C disease.

The therapy has been designed an orphan drug by the U.S. Food and Drug Administration as a potential fragile X treatment. This designation is intended to speed clinical development by providing regulatory support and financial benefits, and to ensure marketing exclusivity for seven years upon regulatory approval.