ASO Therapies 1/3: A New Hope for Rare Diseases

In recent years, ASO (antisense oligonucleotide) therapies have been transforming the landscape of rare genetic diseases. Several treatments have been approved and dozens more are in development. Although we don't yet know whether this approach will be applicable to the LMBRD2 gene, it's important to understand these advances and their implications.

What is an ASO?

An ASO is a short sequence of synthetic nucleotides mimicking RNA or DNA designed to bind specifically to the messenger RNA of a target gene. Think of ASOs as small molecules made in a laboratory that act like "genetic switches."

How do they work? Our genes contain instructions for making proteins in our body. Sometimes, due to a genetic mutation, our body is not able to produce a protein or makes too much of it or produces a faulty protein . For LMBRD2, a faulty protein seems the most likely. ASOs can block these problematic instructions before the protein is made.

Why is this promising? These molecules are attracting a lot of attention because they can be custom-designed to precisely target a specific genetic problem. This opens up potential treatment pathways for genetic diseases that previously had no therapeutic options.

In short: ASOs "turn off" faulty genes before they can cause damage.

The three modes of action of ASOs:

🟣Block

→ Prevent the production of a harmful protein

🟠Modify

→ Correct how the gene is read to produce a better protein

🟢Degrade

→ Destroy the harmful mRNA with or without destroying the normal mRNA (called allele selective ASO ). These types of ASO are likely to be the most appropriate for LMBRD2. Basic research to determine whether mutation are activating mutation (also called gain of function) or dominant negative mutation (the mutant mRNA impairs the function of the normal mRNA) will be needed to choose between a non allele selective degradation (this type of ASO is easier to design but can only be used for gain of function mutations) or an allele selective degradation (design is more challenging but is relevant also for dominant negative mutation

💡The major advantage:

Each ASO is custom-designed to target a specific gene = high specificity of action

A concrete example: Spinal Muscular Atrophy (SMA)

SMA is a rare genetic disease that affects muscles. Before 2016, treatment options were very limited.

The treatment: Spinraza (nusinersen), approved in 2016

How does it work?

• The SMN1 gene doesn't function (this is the cause of the disease)

• There's a "backup" gene called SMN2, but it doesn't produce enough functional protein

• Spinraza modifies how SMN2 is read so it produces more functional protein

• This compensates for the loss of the SMN1 gene

The results:

🟢 Children were able to develop or maintain motor skills

🟢 Significant improvements observed in clinical trials

Why this success?

• Researchers fully understood the disease mechanism

• They knew it was a loss of function (not enough protein)

• The "backup" SMN2 gene offered a clear target for intervention

• Fundamental researches had preceded the treatment's development

The conditions for successful ASO therapy

For an ASO to work, several elements must be in place:

🟣Understand the disease mechanism

→ Know exactly how the mutation causes symptoms

🟠Have a clear target

→ Identify what needs to be blocked, modified, or degraded

🔵Be able to reach affected tissues

→ The ASO must get to where it needs to act

🟢Intervene at an appropriate time

→ Early intervention can prevent irreversible damage, but even later treatment may slow progression or improve quality of life

🟣Chemical stability and safety

→ The ASO must be chemically modified to resist degradation and minimize immune reactions

What about LMBRD2?

Let's be clear: we don't know if ASOs will be a solution for LMBRD2.

Current obstacles:

🔴Unknown gene function

→ What is LMBRD2's exact role in development?

🔴Uncertain pathological mechanism

→ Do mutations cause a lack of protein or a harmful protein?

→ This distinction is crucial for choosing a strategy

🔴Few documented cases

→ Difficult to identify patterns with limited available data

The reality:

For LMBRD2, we're still trying to understand the gene itself. This is the essential first step before even considering any treatment.

Why talk about it then?

🟢Technologies are advancing rapidly

→ Development costs and timelines are decreasing

🟢Fundamental research is the priority

→ Understanding LMBRD2 is the prerequisite for any future treatment

🟢ASOs are just one option among others

→ Gene therapy, small molecules... several approaches exist

What you can do now

🟣Document symptoms

→ Share your child's medical data with us.

🟠Support fundamental research

→ Studies on LMBRD2 function are essential

🔵Join our registry

→ Centralize information at the international level. A mission of our Association.

🟢Collaborate with scientists

→ Facilitate access to samples and data

Conclusion

The example of Spinraza for SMA shows that it's possible to develop treatments for rare genetic diseases. But this success is based on a deep understanding of the disease mechanism, acquired after fundamental researches.

For LMBRD2, we're at this crucial understanding stage. Each family that participates in research helps build this knowledge. It's long-term work, with no guarantee of results, but it's for now the only possible path forward.