Aso Therapies 3/3: The Journey of Developing an ASO Therapy

Introduction

You now understand what ASO therapies are and how they work molecularly. This article answers the question families ask: "What needs to happen before an ASO treatment exists? And if it becomes available, what does it actually involve?"

Based on Dr. Ziegler's presentation to LMBRD2 families, here are the facts.

Why Families Fight for ASO Therapies Research

Before discussing the challenges, let's be clear about why this matters: when ASO therapy works, it transforms lives.

Spinraza for SMA

• In clinical trials, 51% of treated infants achieved motor milestones compared to 0% in the control group, with a 47% reduction in risk of death or permanent ventilation.

• In the NURTURE study of 25 presymptomatic infants: 100% sat without support, 88% walked with assistance. These are children who, without treatment, would never have achieved these milestones.

• Today, over 14,000 patients worldwide are treated with Spinraza.

n-Lorem Foundation (Nano-Rare Diseases)

For diseases affecting fewer than 30 patients worldwide—where traditional drug development is impossible:

• Susannah, diagnosed with KIF1A-associated neurological disorder, experienced 100-290 seizures daily and suffered 26 falls per day. After receiving her personalized ASO treatment, seizures dropped to under 30 per week. She went from using a wheelchair to walking, climbing stairs, and playing basketball with her brother. Published in Nature Medicine, August 2024.

• Over 30 patients treated with personalized ASOs. Nearly all evaluable patients achieved clinically significant benefit, with improvements observed across multiple organs: liver, kidney, eye, and central nervous system.

This is why families pursue ASO research—because for some, it has changed everything.

Now, let's be realistic about what it takes.

Before Any ASO Can Be Designed

You cannot design an ASO from a gene sequence alone. Here's what must be known:

The causal mutation ✅ (LMBRD2: we have this)

The disease mechanism:

• Gain of function or loss of function?

• What happens with 50% protein reduction?

• What happens with 100% reduction?

❌ (LMBRD2: we don't know this yet)

Appropriate cell models carrying the mutation and expressing the mRNA

Appropriate markers to measure if the ASO works

The ASO walk: Testing multiple ASO sequences systematically to find the most effective one

Seven Steps Before Patients Can Be Treated

1. ✅ Identify the causal mutation — LMBRD2: done

2. ❌ Obtain animal models for testing

3. ❌ Identify the most potent and selective ASO

4. ❌ Complete toxicity studies

5. ❌ Define clinical outcomes to measure

6. ❌ Obtain FDA approval (IND)

7. ❌ Obtain ethics board approval (IRB)

LMBRD2 is at step 1 of 7.

What ASO Treatment Actually Involves

Delivery

ASOs do not cross the blood-brain barrier.

For brain diseases: lumbar puncture (spinal tap) every few months

• 30 minutes per injection

• Requires sedation for children

• Complications if scoliosis

• Medical monitoring after each dose

• For life (ASOs degrade over time)

Side Effects

From the drug:

• Low platelets (thrombocytopenia)

• Kidney failure

• Hydrocephalus

• Neuropathy

From the procedure:

• Headaches

• Nerve irritation

The Balance

Yes, there are risks and it's demanding. But for families who've seen children gain abilities through ASO treatment—sitting, walking, seizure reduction—these challenges become worth facing.

What Families Should Know (Dr. Ziegler)

🔴 Experimental — outcomes vary (some patients respond dramatically, others modestly, some not at all)

🔴 Risks — real complications occur (must weigh against potential benefits)

🔴 Anxiety — many uncertainties throughout treatment

🔴 Time commitment — extensive medical appointments

🔴 For life — no endpoint, treatment continues indefinitely

🔴 Strict monitoring — every outcome must be documented

The reality: Not all patients respond equally. But the possibility of improvement is why families choose to try.

Where LMBRD2 Stands

Current status: Fundamental research (understanding what LMBRD2 does)

What we need to know:

• What does the protein do?

• Gain or loss of function?

• Which tissues are affected?

Until we know this: Steps 2-7 cannot begin. No ASO can be designed.

The path forward:

• Complete fundamental research first

• Then determine if ASO technology applies

• If applicable, models like n-Lorem could potentially accelerate development

What helps now:

• Biological samples

• Clinical documentation

• Registry participation

• Funding fundamental research

• International family connections

Conclusion

Article 1: What ASOs are—and Spinraza's transformation of SMA

Article 2: How ASOs work molecularly

Article 3: What it takes to develop them—and what treatment involves

The Complete Picture

ASO therapy development is:

• Long and complex — requires understanding disease biology first

• Demanding — lifelong commitment with real risks

• Uncertain — not all patients respond

• But transformative when it works — 51% of SMA infants achieving motor milestones vs. 0% untreated; nano-rare patients like Susannah going from 100+ daily seizures to under 30 per week

For LMBRD2

ASO treatment is uncertain. We're at the beginning—understanding what LMBRD2 does. This fundamental research cannot be skipped.

But Spinraza and n-Lorem show what's possible. That's why families support research now—to build the foundation that could one day make treatment possible.

Even if ASO treatment becomes available, families should understand what it involves. But they should also understand why it's worth pursuing: because for some families, it has changed everything.

Support fundamental research. Connect with other families. Document your child's journey. Every action builds the knowledge researchers need.

End of ASO series. Thank you for reading.