Vigonvita CDKL5 Deficiency — Preclinical Program

Executive Summary

Vigonvita Therapeutics is developing an AAV-based gene therapy for [CDKL5 deficiency disorder](/genes/cdkl5) (CDD), a rare X-linked neurodevelopmental epilepsy caused by pathogenic variants in the CDKL5 gene. This preclinical program represents one of the most advanced industry-sponsored efforts to develop a CDKL5-directed gene therapy. The company is currently in IND-enabling studies with the goal of entering clinical trials in the near future.

Program Overview

Executive Summary

Vigonvita Therapeutics is developing an AAV-based gene therapy for [CDKL5 deficiency disorder](/genes/cdkl5) (CDD), a rare X-linked neurodevelopmental epilepsy caused by pathogenic variants in the CDKL5 gene. This preclinical program represents one of the most advanced industry-sponsored efforts to develop a CDKL5-directed gene therapy. The company is currently in IND-enabling studies with the goal of entering clinical trials in the near future.

Program Overview

| Parameter | Value |
|-----------|-------|
| Sponsor | Vigonvita Therapeutics |
| Indication | CDKL5 deficiency disorder (CDD) |
| Modality | AAV gene therapy |
| Vector | AAV9 (pending confirmation) |
| Development Stage | Preclinical / IND-enabling |
| Delivery Route | To be determined (likely ICV or ICM) |
| Target Population | Pediatric patients (ages 2+) |

Disease Context: CDKL5 Deficiency Disorder

Clinical Presentation

[CDKL5](/genes/cdkl5) deficiency disorder (CDD) is a devastating neurodevelopmental disorder characterized by:

• Onset: Early infancy (3-12 months), often before 6 months of age
• Seizure types: Multiple types including infantile spasms, focal seizures, myoclonic seizures, tonic-clonic seizures
• Seizure pattern: Often refractory to anti-seizure medications
• Developmental outcome: Severe intellectual disability, limited or absent speech, gross motor impairment
• Core features: Classic Rett-like phenotype with autistic features, movement disorders

Genetics

• Gene: CDKL5 (cyclin-dependent kinase-like 5), located on chromosome Xp22.13
• Inheritance: X-linked dominant, predominantly affecting females
• Male lethality: Most males with pathogenic CDKL5 variants do not survive gestation or die shortly after birth
• Variant types: Missense, nonsense, frameshift, splice site, and large deletions
• Gene size: ~1.5kb coding sequence — fits well within AAV capacity

Epidemiology

• Prevalence: Approximately 1 in 40,000-80,000 live births
• Gender distribution: Overwhelmingly female (approximately 90%)
• Family history: Usually sporadic, though inherited cases documented

Mechanism of Action

Gene Replacement Strategy

Vigonvita's approach uses AAV-mediated delivery of a functional CDKL5 transgene to restore normal CDKL5 protein expression in the central nervous system:

Therapeutic Rationale

• CDKL5 is a kinase critical for neuronal development and function
• Loss-of-function variants cause the characteristic phenotype
• Early intervention may prevent or reduce developmental regression
• Gene replacement aims to restore physiological levels of CDKL5

Preclinical Data

Key Preclinical Findings

| Finding | Relevance |
|---------|-----------|
| CDKL5 expression restored in neurons | Proof-of-concept for gene replacement |
| Dose-dependent expression levels | Supports dose-selection for IND |
| Motor behavior improvements in mouse models | Functional benefit observed |
| No off-target toxicity | Safety profile supports advancement |

Animal Models Used

• Mouse models: Cdkl5 knockout and humanized mouse models
• Endpoints evaluated: Expression, motor function, seizure frequency, survival

Remaining Preclinical Work

• Long-term biodistribution studies
• GLP toxicity studies
• Manufacturing scale-up for clinical supply

Competitive Landscape

CDKL5 Gene Therapy Programs

| Company/Group | Approach | Stage | Status |
|--------------|---------|-------|--------|
| Vigonvita Therapeutics | AAV-CDKL5 | Preclinical | IND-enabling |
| Ultragenyx | AAV-CDKL5 (exploratory) | Preclinical | Research |
| Academic groups (multiple) | AAV-CDKL5 | Research | Active |
| Roche | Small molecule | Discovery | Preclinical |

Comparison: CDKL5 vs. Other NDE Programs

| Feature | CDKL5 (Vigonvita) | Dravet (STK-001) | Angelman (GTX-102) |
|---------|-------------------|------------------|------------------|
| Modality | AAV gene therapy | ASO | ASO |
| Target | CDKL5 | SCN1A | UBE3A-ATS |
| Stage | Preclinical | Phase 1/2 | Phase 1/2 |
| Route | TBD | Intrathecal | Intrathecal |
| Gene size | ~1.5kb | N/A | N/A |

Development Timeline

Anticipated Milestones

| Milestone | Expected Timing |
|----------|---------------|
| IND-enabling studies complete | 2025-2026 |
| IND filing | 2026 |
| Phase 1/2 initiation | 2026-2027 |
| Early efficacy data | 2027-2028 |

Risk Assessment

| Risk Factor | Mitigation |
|------------|-----------|
| Manufacturing scale-up | EarlyCMC engagement |
| Delivery optimization | Non-human primate studies |
| Phenotypic variability | Biomarker development |
| Female-only population | Enrollment strategy |

Regulatory Considerations

Orphan Drug Designation

• Expected: Yes, CDKL5 deficiency qualifies as rare disease
• Benefits: 10-year market exclusivity (US), protocol assistance

Rare Pediatric Disease PRV

• Expected: Yes, if approvable
• Benefits: Priority review voucher (transferable)

Accelerated Pathways

• May qualify for: Breakthrough Therapy Designation, RMAT designation
• Rationale: Severe disease, unmet need, genetic etiology

Cross-Links

• [AAV Gene Therapy for Neurodevelopmental Epilepsy](/therapeutics/aav-gene-therapy-neurodevelopmental-epilepsy)](/therapeutics)
• [CDKL5 Gene](/genes/cdkl5)](/genes)
• [AAV Vectors](/technologies/aav-vectors)](/technologies)
• [Gene Therapy Overview](/technologies/gene-therapy)](/technologies)
• [STK-001 (Dravet) — Phase 1/2 Trial](/clinical-trials/stk001-dravet-syndrome-phase-1-2)
• [GTX-102 (Angelman) — Phase 1/2 Trial](/clinical-trials/gtx102-angelman-syndrome-phase-1-2)