A second Korean NMDA therapy tackles the same problem as AST-001 — But from a different angle

 

SLC6A20-ASO restores NMDA receptor function in SHANK2 and SHANK3 autism models, including adult mice and human brain organoids

 

Lay Summary

A second Korean research programme is now targeting the same NMDA receptor problem as the experimental drug AST-001, but from a different direction.
NMDA receptors are important for learning, communication and social behaviour, and they need two keys to work properly.
One key is glutamate; the second is either glycine or D-serine.
AST-001 provides L-serine, which can potentially increase the availability of D-serine and glycine—the molecules that provide the second key.
The new treatment, SLC6A20-ASO, takes a different approach by reducing the removal of glycine from the brain. This leaves more glycine available to activate NMDA receptors.

In mice with SHANK2 or SHANK3 mutations, SLC6A20-ASO restored NMDA receptor function and improved several autism-related behaviours. Some of these effects occurred in adult mice, suggesting that the signalling problem may remain reversible after development.
The researchers also reproduced the NMDA receptor rescue in human brain organoids carrying SHANK2 or SHANK3 mutations. SHANK3 is particularly important because mutations in this gene cause Phelan-McDermid syndrome.
The two treatments are therefore different, but they may be tackling the same underlying bottleneck: insufficient NMDA receptor co-agonism.
AST-001 has already produced a positive signal in a Phase II autism trial, and a follow-up study found that many previous responders continued to respond after a year.
One Korean reader of this blog has also reported that L-serine appeared to help their child, although this is only an anecdotal observation.

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A few years ago, I became interested in the possibility that NMDA receptor dysfunction might be an important part of autism in at least some people.

That led me to write about AST-001, a Korean drug based on the amino acid L-serine. The results from its Phase II clinical trial were encouraging, and a subsequent long-term study has provided additional evidence that some children who respond may maintain that benefit.

Epiphany: High dose L-Serine to treat children under 7 with severe autism + ID ? It works in Korea

 

Now another Korean research group has reported a fascinating new approach to the same biological system.

The treatment is called SLC6A20-ASO, and unlike AST-001, it does not supply L-serine. Instead, it targets a protein involved in transporting glycine, another important molecule involved in NMDA receptor activation. 

Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids | Nature Communications

 

The two approaches are therefore different, but they may be trying to solve the same underlying problem: insufficient NMDA receptor co-agonism.

That makes the new study particularly interesting.

 

The NMDA receptor has two keys

To understand why these two therapies might be related, it helps to think of an NMDA receptor as a door with two keys.

One key is glutamate.

The second key is either glycine or D-serine.

Both keys are needed for the receptor to open properly.

So you can have plenty of glutamate, but if there isn't enough of the second key, NMDA receptor signalling can still be reduced.

This is called NMDA receptor hypofunction.

The important point is that AST-001 and SLC6A20-ASO approach this second key from different directions.

 

AST-001: helping provide the second key

AST-001 is a pharmaceutical formulation of L-serine.

L-serine is not itself the second key. Instead, it is a precursor that can contribute to the production of D-serine and glycine, both of which can act at the NMDA receptor co-agonist site.

So the simplified idea is:

L-serine

↓

D-serine / glycine pathways

↓

more potential availability of the second NMDA key

↓

greater NMDA receptor activation

 

This was one of the possible mechanisms I discussed in my earlier article about AST-001.

The important thing is that this is a potential mechanism, not something the clinical trial definitively proved.

 

What happened with AST-001?

The original Phase II trial was conducted in 151 children aged 2–11 years with autism.

The high-dose AST-001 group showed a statistically significant improvement in the Vineland Adaptive Behavior Composite, a measure of adaptive functioning, compared with the placebo-to-high-dose control group.

There was also an improvement in the Clinical Global Impression-Severity measure.

One particularly interesting observation was that the younger children appeared to benefit more strongly, especially those aged 2–6 years. This was a subgroup finding, however, and should not be interpreted as proof that AST-001 only works in younger children.

Since then, there has been a 52-week follow-up study.

The follow-up included 61 children who had previously responded to treatment. Among the 48 children who had been classified as CGI-I responders at week 24, 45 continued to meet the responder criteria at week 52.

The treatment was also generally well tolerated.

This is encouraging, although the long-term study did not include a concurrent placebo group and therefore cannot prove that the improvement over the year was entirely due to AST-001.

So AST-001 is still an investigational treatment, but the evidence is becoming increasingly interesting.

 

And one reader of this blog actually tried L-serine

There is also an interesting real-world observation from this blog.

A Korean reader who had followed the AST-001 research told me that they tried L-serine and found that it appeared to help their child.

Obviously, this is only an anecdote.

It cannot establish that L-serine caused the improvement, and there was no placebo control or blinded assessment.

But it is interesting to record because it is consistent with the direction of the clinical research.

We now have a positive Phase II signal, encouraging long-term follow-up among previous responders, and at least one independent experience reported to this blog.

That certainly doesn't prove that L-serine works for autism generally.

But it makes the AST-001 story worth following.

 

Now comes the second Korean NMDA approach

The new study comes from the Institute for Basic Science (IBS) Center for Synaptic Brain Dysfunctions in South Korea.

The researchers were interested in glycine, the other molecule that can provide the second key for the NMDA receptor.

They focused on a protein called SLC6A20, which transports glycine.

Their idea was remarkably simple:

What if you prevent some of the glycine from being transported away?

More glycine would then remain available around NMDA receptors.

The researchers used an antisense oligonucleotide, or ASO, to reduce production of SLC6A20.

This is very different from giving a glycine supplement.

The ASO is a highly targeted molecular intervention designed to reduce expression of a particular protein.

 

SLC6A20-ASO: protecting the second key

The simplified mechanism is therefore:

 

SLC6A20 inhibition

↓

less glycine transported away

↓

more local glycine available

↓

more of the second NMDA key

↓

restored NMDA receptor function

 

So we now have two approaches:

AST-001

L-serine → D-serine/glycine pathways → potentially more NMDA co-agonism

SLC6A20-ASO

less glycine transport → more local glycine → more NMDA co-agonism

Different approaches for the same biological bottleneck.

That is what makes the new study so interesting in the context of AST-001.

 

Testing the idea in SHANK2 and SHANK3 autism models

The researchers tested SLC6A20-ASO in mice carrying mutations in SHANK2 and SHANK3.

These are important autism-associated genes involved in the organisation and function of excitatory synapses.

SHANK3 is particularly relevant to Phelan-McDermid syndrome, where loss or disruption of one copy of SHANK3 can produce a neurodevelopmental disorder with autism, intellectual disability and other features.

The researchers found that the SHANK2 and SHANK3 mutant mice had reduced NMDA receptor function.

After SLC6A20-ASO treatment, NMDA receptor function was restored.

And the effects were not limited to electrical measurements.

Several autism-related behavioural abnormalities also improved.

 

The adult-mouse finding

Perhaps the most striking part of the study was that the treatment worked in adult mice.

The researchers were not simply preventing a developmental abnormality from occurring.

They were intervening after the animals had already developed.

The treatment improved several social, communication and repetitive behaviours, although it did not correct every abnormal behaviour in every model.

That distinction is important.

This is not evidence that autism can simply be "reversed" in adulthood.

But it does suggest that at least some of the consequences of these genetic mutations remain functionally modifiable after development.

The underlying mutation remains.

The researchers are instead correcting a downstream signalling problem.

 

Then they tested human brain organoids

The researchers went one step further.

Using CRISPR gene editing, they created human cortical organoids carrying SHANK2 or SHANK3 mutations.

These human brain models showed reduced NMDA receptor function.

They then used an ASO designed to target human SLC6A20.

Again, NMDA receptor function was restored towards normal levels.

This is important because the same basic mechanism was seen in genetically modified mice and human cortical organoids.

It is still very early-stage research, but it gives the finding greater human relevance than a mouse study alone.

 

Could this identify a subgroup of autism?

This may ultimately be the most important question.

The new study does not suggest that every autistic person has insufficient NMDA receptor activity.

Autism is biologically heterogeneous.

Some people may have NMDA hypofunction.

Others may have different forms of synaptic dysfunction.

And the same individual could potentially have different abnormalities in different brain regions.

This means that simply increasing NMDA receptor activity is unlikely to be a universal treatment for autism.

The more interesting possibility is that we might eventually identify people whose autism involves NMDAR hypofunction or inadequate co-agonism.

For those people, treatments such as L-serine or more targeted approaches affecting glycine availability could potentially be more relevant.

 

Why the story is becoming more interesting

When I first wrote about AST-001, the idea that L-serine might improve autism through NMDA receptor signalling was still speculative.

The Phase II trial provided an encouraging clinical signal.

The longer-term follow-up has added evidence that previous responders can continue to show benefit.

And now a completely different intervention—SLC6A20-ASO—has restored NMDA receptor function in genetic models involving SHANK2 and SHANK3, including adult mice and human cortical organoids.

This does not prove that AST-001 works because of glycine.

It does not prove that SLC6A20-ASO will work in humans.

And it certainly does not mean that NMDA receptor modulation is the answer for everyone with autism.

But the two lines of research are beginning to tell a coherent story.

Different interventions may be approaching the same biological bottleneck from different directions.

For AST-001, the starting point is L-serine.

For SLC6A20-ASO, the starting point is glycine transport.

But the destination may be the same:

restoring NMDA receptor co-agonism when that particular signalling system is not functioning properly.

What about using D-serine?

D-serine is particularly interesting because it is one of the actual "second keys" that can activate an NMDA receptor. Unlike AST-001, which supplies L-serine, D-serine can act directly at the NMDA receptor co-agonist site. In theory, this makes D-serine a more direct way of increasing NMDA receptor activation.

However, there has been a safety concern with D-serine, particularly dose-related kidney toxicity seen in animal studies. Human studies so far have been more reassuring, but D-serine still requires appropriate safety monitoring. L-serine therefore has an important potential advantage: it can provide a more indirect and potentially safer way of influencing the same system.

This may be one reason why AST-001 uses L-serine rather than D-serine.

Why might glycine itself not work?

If glycine is the second key for the NMDA receptor, it is natural to ask: why not simply take glycine?

The problem is that the amount of glycine reaching an individual NMDA receptor is tightly regulated by transporters that remove glycine from the extracellular space.

So taking more glycine does not necessarily mean that more glycine will reach the particular synapses where NMDA receptors are under-functioning.

There is also an important complication: glycine has two very different roles in the nervous system. It can enhance NMDA receptor activity, but it also acts as an inhibitory neurotransmitter, particularly in the brainstem and spinal cord.

This means that simply increasing glycine throughout the nervous system may not be the ideal strategy.

The SLC6A20 researchers took a more targeted approach: instead of supplying large amounts of glycine, they reduced a transporter involved in glycine handling, potentially allowing more glycine to remain available where it is needed.

This does not prove that oral glycine cannot work. It simply means that the new study has not tested that question.

The important distinction is therefore:

Glycine supplementation = increase the supply

SLC6A20 inhibition = change how the brain handles the glycine already present

The latter may ultimately prove a more precise way of providing the second key to the NMDA receptor.