Splice Modulation Therapy for Neurodegeneration

Overview

This therapeutic strategy targets spliceosome dysregulation—a hallmark of multiple neurodegenerative diseases—to restore proper mRNA splicing patterns and rescue neuronal function. Small molecule splice modulators can correct aberrant splicing events that produce toxic protein isoforms or disrupt essential neuronal gene expression.

[@spliceosome2023][@tdp2022]

Target

• Primary Target: Spliceosome complex (U1 snRNP, SF3B1, SRSF2, hnRNPs)
• Target Type: Small molecule splice modulator / RNA-binding oligonucleotide
• Expression: Ubiquitous spliceosome machinery with neuron-specific vulnerability to splice dysregulation

Mechanistic Rationale

Spliceosome dysfunction is increasingly recognized as a key contributor to neurodegeneration:

ALS/FTD

• [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology disrupts splicing of thousands of transcripts
• C9orf72 hexanucleotide repeat produces toxic DPR proteins through aberrant splicing
• STMN2 splicing disruption causes axonal degeneration
• Correction of splice patterns can restore neuronal viability

Alzheimer's Disease

• [APOE](/proteins/apoe) splicing isoform imbalances affect lipid metabolism
• [tau](/proteins/tau) isoform ratios influence aggregation propensity
• Synaptic protein mis-splicing impairs neurotransmission

Parkinson's Disease

• SNCA exon skipping produces aggregation-resistant isoforms
• LRRK2 splice variants affect kinase activity
• GBA1 splicing impacts lysosomal function

Therapeutic Approach

...

Overview

This therapeutic strategy targets spliceosome dysregulation—a hallmark of multiple neurodegenerative diseases—to restore proper mRNA splicing patterns and rescue neuronal function. Small molecule splice modulators can correct aberrant splicing events that produce toxic protein isoforms or disrupt essential neuronal gene expression.

[@spliceosome2023][@tdp2022]

Target

• Primary Target: Spliceosome complex (U1 snRNP, SF3B1, SRSF2, hnRNPs)
• Target Type: Small molecule splice modulator / RNA-binding oligonucleotide
• Expression: Ubiquitous spliceosome machinery with neuron-specific vulnerability to splice dysregulation

Mechanistic Rationale

Spliceosome dysfunction is increasingly recognized as a key contributor to neurodegeneration:

ALS/FTD

• [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology disrupts splicing of thousands of transcripts
• C9orf72 hexanucleotide repeat produces toxic DPR proteins through aberrant splicing
• STMN2 splicing disruption causes axonal degeneration
• Correction of splice patterns can restore neuronal viability

Alzheimer's Disease

• [APOE](/proteins/apoe) splicing isoform imbalances affect lipid metabolism
• [tau](/proteins/tau) isoform ratios influence aggregation propensity
• Synaptic protein mis-splicing impairs neurotransmission

Parkinson's Disease

• SNCA exon skipping produces aggregation-resistant isoforms
• LRRK2 splice variants affect kinase activity
• GBA1 splicing impacts lysosomal function

Therapeutic Approach

Splice-switching oligonucleotides (SSOs): Antisense oligonucleotides that block splicing enhancers/suppressors to redirect splicing

Small molecule modulators: Drugs like E7107, H3B-8800 (currently in cancer trials) that modulate spliceosome activity

U1 snRNP restoration: Enhance U1 function to correct 5' splice site recognition

hnRNP modulation: Target hnRNP A1/A2 to restore splicing balance

Delivery Feasibility

• Oligonucleotides: Require CNS delivery via intrathecal or intranasal routes; LNP or AAV delivery under development
• Small molecules: [Blood-brain barrier](/entities/blood-brain-barrier) penetration varies by compound; E7107 has limited BBB crossing
• Novel approaches: Splice-modulating ASO conjugates with brain-targeting peptides

Safety Considerations

• On-target toxicity: Broad splice modulation affects essential genes
• Therapeutic window: Selective modulation of disease-relevant splicing events required
• Off-target effects: Careful sequence design needed for SSOs

Combination Potential

• + [Autophagy](/entities/autophagy) inducers: Enhanced clearance of misfolded proteins from corrected splicing
• + Proteostasis modulators: Synergistic restoration of protein homeostasis
• + Gene therapy: Direct delivery of corrected splice isoforms

Biomarkers

• Direct: mRNA-seq to quantify splice event correction
• Indirect: Protein isoform ratios in CSF (e.g., tau 3R/4R ratio)
• Clinical: [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL) for disease progression

Ranking Score

| Dimension | Score | Rationale |
|-----------|-------|-----------|
| Novelty | 9 | Novel therapeutic approach not yet in clinical trials for neurodegeneration |
| Mechanistic Rationale | 8 | Strong evidence for splice dysregulation across AD, PD, ALS, FTD |
| Root-Cause Coverage | 7 | Addresses upstream dysregulation rather than downstream aggregation |
| Delivery Feasibility | 5 | BBB remains challenge; intrathecal feasible but invasive |
| Safety Plausibility | 6 | On-target risks require precise targeting |
| Combinability | 8 | Synergistic with proteostasis and autophagy approaches |
| Biomarker Availability | 7 | mRNA-seq enables direct measurement of splice correction |
| De-risking Path | 5 | Cancer trials provide initial safety data; CNS-specific data needed |
| Multi-disease Potential | 9 | Applicable to ALS, FTD, AD, PD |
| Patient Impact | 8 | High unmet need in genetic forms (C9orf72, TARDBP) |
| Total | 72/100 | |

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Actionable Next Steps

Lab Experiments (Proof-of-Concept & Target Validation)

iPSC Neuron Validation

• Obtain iPSC lines from C9orf72, TARDBP, and sporadic ALS/FTD patients
• Differentiate to motor [neurons](/entities/neurons) and cortical neurons
• Measure: splice patterns (RNA-seq), TDP-43 localization, STMN2 splicing, neuronal viability
• Test SSO delivery via lipid nanoparticles or AAV9
• Timeline: 4-6 months
• Estimated cost: $150,000-200,000

SSO Lead Optimization

• Design splice-switching oligonucleotides targeting disease-relevant exons:
• C9orf72 intron 1b (reduce toxic DPR translation)
• STMN2 exon 2a (restore axonal stability)
• Tau exon 10 (balance 3R/4R ratio for AD)
• In vitro screening in patient-derived neurons
• Timeline: 6-9 months
• Estimated cost: $300,000-500,000

Small Molecule Modulator Repurposing

• Screen FDA-approved drugs for splice-modulating activity
• Focus on CNS-penetrant compounds
• Test in ALS/FTD model systems
• Timeline: 3-4 months
• Estimated cost: $100,000-150,000

Clinical Protocol Design

First-in-Human Study Design

• Phase 1: Dose escalation in healthy volunteers (if SSO) or cancer patients (if small molecule)
• Phase 1b: Patients with confirmed TDP-43 pathology (CSF biomarker positive)
• Key biomarkers: CSF splice junction reads, NfL, phosphorylated TDP-43
• Timeline: 24-36 months for Phase 1/2
• Estimated cost: $5-10M

Patient Population

• Genetically confirmed C9orf72 carriers (early symptomatic)
• TARDBP mutation carriers
• Sporadic ALS/FTD with TDP-43 pathology
• Target enrollment: 30-50 patients

Regulatory Strategy

• Orphan drug designation for rare genetic forms
• Fast track for life-threatening indication
• Parallel consultation with FDA/EMA

Partnership Targets

| Partner Type | Target Organization | Rationale |
|-------------|---------------------|-----------|
| Pharma | Biogen, Ionis | Existing ASO platform and ALS pipeline |
| Pharma | Roche, PTC | Small molecule CNS capabilities |
| Biotech | Wave Life Sciences | Stereopure ASO technology |
| Academic | University of Miami Brain Bank | C9orf72 patient tissue |
| Academic | NIH RAID program | Preclinical screening resources |
| VC | ARCH, Polaris, Third Rock | Neurodegeneration-focused |

Cross-Links

Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [ALS](/diseases/amyotrophic-lateral-sclerosis)
• [FTD](/diseases/frontotemporal-dementia)
• [Huntington's Disease](/diseases/huntingtons)

Mechanisms

• [Spliceosome in Neurodegeneration](/mechanisms/spliceosome-neurodegeneration)
• [RNA Splicing Mechanisms](/mechanisms/rna-splicing-mechanisms)
• [Gene Expression Dysregulation](/mechanisms/gene-expression-dysregulation)
• [RNA Metabolism](/mechanisms/rna-metabolism)
• [Protein Isoform Dysregulation](/mechanisms/protein-isoform-dysregulation)
• [Epigenetic Regulation](/mechanisms/epigenetic-regulation)

Proteins & Genes

• [TDP-43](/proteins/tdp-43)
• [FUS](/entities/fus)
• [SOD1](/entities/sod1)
• [C9orf72](/entities/c9orf72)
• [HNRNPA1](/genes/hnrnpa1)

Cell Types

• [Motor Neurons](/cell-types/motor-neurons)
• [Neurons](/cell-types/neurons)
• [Astrocytes](/cell-types/astrocytes)
• [Oligodendrocytes](/cell-types/oligodendrocytes)

Treatments

• [Antisense Oligonucleotide Therapy](/therapeutics/antisense-oligonucleotide-therapy)
• [Gene Therapy](/therapeutics/gene-therapy)
• [Small Molecule Therapy](/therapeutics/small-molecule-therapy)

Rubric Score

| Dimension | Score | Rationale |
|-----------|-------|-----------|
| Novelty | 8/10/10 | Splice-modulating therapies are novel; antisense oligonucleotides for splicing in CNS emerging |
| Mechanistic Rationale | 7/10/10 | Can correct splice defects, restore protein isoforms; precise mechanism for neurodegeneration |
| Addresses Root Cause | 7/10/10 | Addresses genetic regulation; can target disease-causing splice variants |
| Delivery Feasibility | 5/10/10 | ASO delivery to brain challenging; intrathecal administration needed |
| Safety Plausibility | 6/10/10 | Off-target splicing effects possible; requires careful design |
| Combinability | 6/10/10 | Combines with gene therapy and traditional small molecules |
| Biomarker Availability | 6/10/10 | Splice products measurable via RNA sequencing; biomarker development ongoing |
| De-risking Path | 7/10/10 | ASO platform established; several CNS trials ongoing |
| Multi-disease Potential | 7/10/10 | Relevant for genetic forms of AD, PD, ALS, Huntington disease |
| Patient Impact | 7/10/10 | Could provide disease-modifying effects for genetically predisposed patients |
| Total | 66/100 | |

Related Pages

• [Spliceosome and Neurodegeneration](/diseases/neurodegeneration)
• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy) — Related pathology
• [C9orf72 RNA-Targeting for DPR Reduction](/diseases/amyotrophic-lateral-sclerosis)
• ASO Therapy — Delivery modality

Implementation Roadmap

Estimated Timeline (4-6 years to IND)

| Phase | Duration | Key Milestones |
|-------|----------|----------------|
| Lead Optimization | 6-12 months | Screen candidates, optimize PK/PD |
| Preclinical (IND-enabling) | 18-24 months | GLP toxicology, efficacy in models, GMP manufacturing |
| IND-enabling studies | 12-18 months | GLP toxicology, CMC, regulatory meetings |
| Phase I | 12-18 months | Safety, dose-ranging in patients |

Estimated Cost

• Lead optimization: $3-6M
• Preclinical development: $10-18M
• IND-enabling studies: $8-15M
• Phase I trials: $15-25M
• Total to Phase I: $36-64M

Academic Centers

University of Pennsylvania — Dr. John Trojanowski

Stanford University — Dr. Marion Buckwalter

UCLA — Dr. Varghese John

University of Michigan — Dr. Henry Paulsen

Karolinska Institutet — Dr. Tomas M barek

Potential Industry Partners

Biogen — Neuroscience pipeline

Roche — CNS portfolio

Merck — Neuroscience division

Takeda — Neuroscience acquisitions

AbbVie — CNS programs

Risk Assessment

| Risk | Likelihood | Impact | Mitigation |
|------|------------|--------|------------|
| Brain penetration failure | Medium | High | Early PK/PD screening |
| Off-target effects | Low | Medium | Selectivity profiling |
| Clinical trial recruitment | Low | Medium | Multi-center design |

Regulatory Strategy

• Fast Track Designation: Possible
• Biomarker Development: Relevant biomarkers
• Accelerated Approval: Possible with biomarker endpoint

References

[Unknown, Spliceosome dysfunction in neurodegenerative disease (2023) (2023)](https://doi.org/10.1016/j.tins.2023.01.005)

[Unknown, TDP-43 and RNA splicing in ALS (2022) (2022)](https://doi.org/10.1038/s41582-022-00670-5)

[Unknown, Splice-modulating oligonucleotides in neurological disease (2024) (2024)](https://doi.org/10.1038/s41582-023-00894-9)

[Unknown, SF3B1 mutations and neural dysfunction (2023) (2023)](https://doi.org/10.1093/brain/awab456)

[Unknown, C9orf72 splicing therapy approaches (2023) (2023)](https://doi.org/10.1126/sciadv.ade5077)

[Unknown, E7107 and spliceosome modulation (2020) (2020)](https://doi.org/10.1158/1538-7445.AM2020-4432)

Pathway Diagram

The following diagram shows the key molecular relationships involving Splice Modulation Therapy for Neurodegeneration discovered through SciDEX knowledge graph analysis: