Targeting IGF-2R Receptor a Potential Therapy Approach, Mouse Study Shows

Activating the insulin‐like growth factor 2 receptor, or IGF-2R — a cell surface receptor involved in protein trafficking and degradation within cells — partially or completely corrected cognitive, motor, and behavioral deficits in a mouse model of Angelman syndrome, a study shows.

Notably, these benefits were observed with the administration of either IGF‐2 or mannose‐6‐phosphate (M6P), two of the receptor’s ligands. IGF-2 also was associated with a significant reduction in repetitive behaviors and seizures.

Treatment with either ligand — both signaling proteins that bind to a receptor— also appeared to be safe.

These findings highlighted that activating IGF-2R may be a potentially safe and effective therapeutic approach for Angelman syndrome.

The study, “CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice,” was published in the journal Autism Research.

A complex genetic condition, Angelman is characterized by delayed development, intellectual disability, seizures, speech impairment, lack of sleep, and problems with movement and balance.

It is caused by a deficiency of the UBE3A protein in the brain. UBE3A targets proteins to be broken down within cells and is thought to play a key role in the normal development and function of the central nervous system (CNS), comprised of the brain and spinal cord.

“Although much remains to be understood about the mechanisms altered in the CNS of AS [Angelman syndrome] patients, it is clear that therapeutics aimed at restoring healthy synaptic and neuronal functions would be clinically valuable,” the researchers wrote. Of note, synapses are the points of close contact between nerve cells that allow them to communicate.

Now, a team of researchers in the U.S. have discovered that activating a cell surface receptor called IGF‐2R may be a potential therapeutic approach for Angelman.

IGF‐2R, also known as the cation-independent M6P receptor (CIM6PR), is involved in protein trafficking and degradation. Its impairment has been associated with neuronal and synaptic dysregulation, or improper functioning.

Additionally, previous studies have highlighted that IGF‐2R activation by one of its ligands, IGF-2, has neuroprotective effects, improving synaptic function and memory in healthy mice, and reversing cognitive, social, and behavioral problems in a mouse model of autism spectrum disorders (ASDs).

The researchers first analyzed the levels of IGF-2R, premature IGF-2, and mature, functional IGF-2 in the hippocampus — a brain region involved in learning and memory, and affected in Angelman — in a mouse model of the disease and in healthy mice.

They found that while IGF-2R and mature IGF-2 levels were not significantly different between the mice, premature IGF-2 was significantly accumulated in the hippocampus of the mouse model.

This suggested that IGF-2 production, processing, transport, and/or degradation are impaired in mice with Angelman-like disease, the team noted, adding that “future studies are needed to understand these alterations.”

The team then evaluated whether activating IGF-2R with IGF‐2 or M6P — another ligand that binds to a different site of the receptor — could lessen cognitive and motor deficits, as well as repetitive behaviors and seizures, in the mouse model.

The mice received an under-the-skin injection of either one of the two IGF-2R ligands (IGF-2 or M6P), or a corresponding placebo. A battery of behavioral, cognitive, motor, and seizure-induction tests was performed 20 minutes after treatment.

The results showed that treatment with either ligand significantly reduced or totally reversed Angelman-like cognitive deficits, working memory/flexibility problems, and motor deficits in these mice.

Treating mice with IGF-2, but not M6P, also corrected repetitive behaviors and significantly lessened induced seizures.

“It remains to be determined whether other doses of M6P may have a positive effect,” or whether the ligands have indeed different effects, the researchers wrote.

Where multiple tests were conducted, including some related to cognitive and motor function, the positive impacts of the treatments persisted for days.

“The beneficial effects of the CIM6P/IGF-2R ligands on the variety of AS deficits indicate that they target multiple brain functions in a variety of brain regions,” the researchers wrote.

Moreover, an additional observational battery of tests, including physical, behavioral, and neurological evaluations, showed no significant differences between healthy mice and mice with Angelman-like disease treated with IGF-2 or M6P, up to seven days after injection.

These findings suggested that treatment with two IGF-2R ligands is generally safe and “effective in significantly reversing most of the major deficits of AS modeled in mice,” the team added.

While the underlying mechanisms of these therapeutic benefits remain unclear and future studies are needed to clarify them, the team hypothesized that they may be related to IGF-2R’s role in protein metabolism, particularly protein degradation.

“Our data provide strong preclinical evidence that targeting CIM6P/IGF‐2R is a promising approach for developing novel therapeutics for AS,” the researchers concluded.

They also noted that, because IGF-2 treatment also corrects several deficits in a mouse model of ASD, activating IGF-2R may promote significant therapeutic benefits in several ASDs.