cdnf-therapy-parkinsons

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cdnf-therapy-parkinsons

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">cdnf-therapy-parkinsons</th>
</tr>
<tr>
<td class="label">Trial ID</td>
<td>NCT05823401</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>AAV-CDNF (AAV2-CDNF)</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase 1/2</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Active</td>
</tr>
<tr>
<td class="label">Indication</td>
<td>Parkinson's Disease</td>
</tr>
<tr>
<td class="label">Delivery</td>
<td>Intraparenchymal (intraputaminal)</td>
</tr>
<tr>
<td class="label">Sponsor</td>
<td>Herantis Pharma</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>Target</td>
</tr>
<tr>
<td class="label">CDNF</td>
<td>Dopaminergic neurons</td>
</tr>
<tr>
<td class="label">GDNF</td>
<td>Dopaminergic neurons</td>
</tr>
<tr>
<td class="label">BDNF</td>
<td>Broad neuronal</td>
</tr>
<tr>
<td class="label">NRTN (Neurturin)</td>
<td>Dopaminergic neurons</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>CDNF (Original)</td>
</tr>
<tr>
<td class="label">Delivery</td>
<td>Intraparenchymal (brain surgery)</td>
</tr>
<tr>
<td class="label">Invasiveness</td>
<td>High ( stereotactic surgery)</td>
</tr>
<tr>
<td class="label">Patient Acceptance</td>
<td>Low (requires brain implant)</td>
</tr>
<tr>
<td class="label">Development Status</td>
<td>Phase

...

cdnf-therapy-parkinsons

Overview

CDNF Therapy for Parkinson's Disease is a therapeutic approach or intervention being investigated for neurodegenerative diseases. This page reviews the scientific rationale, preclinical and clinical evidence, dosing considerations, and current status of research. [@lindholm2007]

Cerebral Dopamine Neurotrophic Factor (CDNF) is a novel neurotrophic factor that has shown promise in protecting and restoring dopaminergic [neurons](/entities/neurons) in Parkinson's Disease (PD) models. CDNF represents a potential disease-modifying therapy that targets the underlying neurodegeneration rather than just managing symptoms. [@voutilainen2009]

Mechanism of Action

CDNF is a secreted protein belonging to the conserved neurotrophic factor family. Its mechanism of action includes: [@zhang2015]

Neuroprotection: CDNF protects dopaminergic neurons from degeneration in the substantia nigra pars compacta [1]

Neurorestoration: Promotes regeneration and functional recovery of damaged dopaminergic neurons [2]

Anti-inflammatory: Reduces neuroinflammation in PD models [3]

Anti-apoptotic: Prevents programmed cell death in dopaminergic neurons [4]

Synaptic Plasticity: Enhances synaptic function and dopamine release [5]

CDNF exerts its effects through binding to specific receptors on dopaminergic neurons, activating downstream signaling pathways that promote neuronal survival and function. The primary signaling pathways include: [@chmielarz2017]

MAPK/ERK pathway: Involved in neuronal survival and differentiation
PI3K/Akt pathway: Critical for cell survival signaling
cAMP/PKA pathway: Regulates synaptic plasticity and neurotransmitter synthesis

Preclinical Evidence

Animal Studies

Multiple preclinical studies have demonstrated CDNF's efficacy in PD models: [@baruah2020]

6-OHDA Rat Model: CDNF administration led to significant protection of dopaminergic neurons and improvement in behavioral deficits [6][7]
MPTP Mouse Model: CDNF reduced dopaminergic neuron loss and improved motor function [8][9]
Alpha-Synuclein Models: CDNF showed protective effects against alpha-synuclein-induced neurotoxicity [10]
Rotenone Model: Protection against mitochondrial toxin-induced degeneration [11]

Mechanism Studies

Research has shown that CDNF: [@lindholm2012]

Upregulates tyrosine hydroxylase (TH) expression [12]
Increases dopamine levels in the striatum [13]
Activates MAPK/ERK and PI3K/Akt signaling pathways [14]
Reduces oxidative stress markers [15]
Modulates [autophagy](/entities/autophagy) pathways [16]

Clinical Trial Status

Phase 1-2 Clinical Trial (NCT01362994)

Herantis Pharma conducted a first-in-human study of CDNF in Parkinson's disease patients: [@sidorova2019]

Study Design: Multi-center, double-blind, randomized, placebo-controlled
Participants: Patients with moderate Parkinson's disease (Hoehn & Yahr stages 2-3)
Delivery Method: Intraparenchymal infusion directly to the brain via stereotactic surgery
Primary Outcome: Safety and tolerability
Secondary Outcomes: Motor function assessment (UPDRS parts II and III) [17]
Locations: Three university hospitals in Sweden and Finland
Treatment Duration: 12-month treatment period completed; patients now in 1-year follow-up study

Phase 1-2 Results Summary

The Phase 1-2 trial results demonstrated:

Safety Profile: CDNF is safe and well-tolerated. No serious adverse events related to the treatment were reported during the trial period. [@slevin2020] [@huttunen2022]
Efficacy Signals: Preliminary data suggested potential benefits in motor function
Dose Selection: Established maximum tolerated dose for future studies
Delivery Feasibility: Intraparenchymal infusion was surgically feasible and safe [20]

AAV-CDNF Gene Therapy Program

Building on the CDNF protein experience, Herantis Pharma developed an AAV-delivered gene therapy approach to enable sustained, local CDNF expression in the brain.

Clinical Trial: NCT05823401

Mechanism: ER Stress Reduction

AAV-CDNF leverages CDNF's unique mechanism of action targeting endoplasmic reticulum (ER) stress — a central pathological feature in neurodegenerative diseases:

Mermaid diagram (expand to render)

Why ER stress matters for neurodegeneration:

Tau pathology in 4R-tauopathies (CBS/PSP) causes significant ER stress
Alpha-synuclein aggregation activates the unfolded protein response (UPR)
Chronic ER stress leads to neuronal apoptosis via CHOP pathway
CDNF directly modulates the UPR to promote cell survival

Preclinical Data

6-OHDA Model: AAV-CDNF protected dopaminergic neurons with effect sizes >50%
MPTP Model: Reduced neuron loss and improved motor function
BBB Modulation: AAV2.7m8-CDNF enables intravenous delivery with BBB modulation (preclinical)

Relevance to CBS/PSP

The AAV-CDNF approach is particularly relevant to atypical parkinsonism because:

Tau-induced ER stress: CBS/PSP feature prominent tau pathology that causes ER stress

CDNF's unique mechanism: Unlike GDNF (RET receptor), CDNF targets the UPR directly

Combination potential: Could be combined with anti-tau immunotherapies

Ongoing Studies

NCT05823401: Phase 1/2 AAV-CDNF for PD (active)
Follow-on studies: Planning for CBS/PSP indication pending PD results

Ongoing and Planned Studies

HER-096 Phase 2: Planned based on positive Phase 1b results (October 2025)
Continued preclinical CDNF research for understanding mechanism
Biomarker development for patient selection and response prediction
Combination therapy studies with standard PD medications

Delivery Method

CDNF is delivered via intraparenchymal infusion, a surgical procedure that involves: [@mud2013]

Stereotactic Targeting: Precise targeting of the putamen using MRI-guided stereotaxy [21]

Cannula Implantation: Permanent infusion cannula placed bilaterally

Continuous Infusion: Slow, continuous delivery of CDNF over extended periods

Pump System: Implantable pump system allows controlled, continuous drug delivery [22]

This delivery method bypasses the [blood-brain barrier](/entities/blood-brain-barrier) and provides direct neurotrophic support to the affected brain regions. The putamen was chosen as the target because it is the primary region where dopaminergic neurons terminate and is critically affected in PD. [@zhang2013]

Surgical Considerations

Requires stereotactic neurosurgery expertise
Bilateral implantation typically performed
Pump placement in subcutaneous tissue
Regular refilling of drug reservoir required

Safety Profile

The safety profile established in clinical trials includes: [@domanskyi2015]

Common Adverse Events (Mild to Moderate)

Headache (most common, reported in >50% of subjects)
Surgical site discomfort
Transient mild neurological symptoms
Post-operative confusion (usually resolved within 24-48 hours)

Safety Considerations

No dose-limiting toxicities observed [23]
No immunogenicity concerns reported
Surgical risks are manageable with standard stereotactic neurosurgery protocols
No worsening of baseline PD symptoms attributed to CDNF

Comparison to Other Neurotrophic Factors

CDNF belongs to a family of neurotrophic factors being investigated for PD. Key comparisons include: [@airavaara2009]

CDNF has shown a favorable safety profile compared to some other neurotrophic factors that have encountered challenges in clinical translation. Unlike GDNF, CDNF appears to have better distribution properties and does not require as precise targeting [24]. [@huttunen2022]

Challenges and Limitations

Current Challenges

Invasive delivery required (brain surgery)
Limited long-term safety data
Optimal dosing regimen not yet established
Patient selection criteria need refinement

Future Directions

Development of less invasive delivery methods
Protein engineering for improved pharmacokinetics
Gene therapy approaches for sustained expression
Combination with neuroprotective small molecules

Pipeline Update: CDNF to HER-096 Transition

Critical Development: Herantis Pharma has transitioned from CDNF protein therapy to HER-096, a small molecule analog designed to replicate CDNF's mechanism of action. This transition addresses the major limitation of CDNF (requiring invasive brain surgery) with a subcutaneous injection approach.

HER-096 Clinical Development Timeline

Phase 1a (Healthy Subjects): Completed October 2023
Single ascending subcutaneous doses across 6 dose groups (60 participants: ages 20-45 and 50-75)
Good safety and tolerability profile
CSF concentrations reached 50-100 ng/ml within 4-12 hours post-dose (200 mg)
Plasma half-life: ~2 hours (young adults), ~2.5 hours (older adults)
Phase 1b: Completed October 2025
Repeated dosing: 200 mg and 300 mg, twice-weekly over 4 weeks
Part 1: 12 healthy volunteers
Part 2: 24 Parkinson's disease patients
Key findings: Drug was safe and well tolerated; blood-brain barrier penetration confirmed; 300 mg dose identified as suitable for Phase 2
Phase 2: Planned (based on positive Phase 1b topline results)

Advantages of HER-096 over CDNF

Related pages: [GDNF Therapy](/therapeutics/gdnf-therapy-parkinsons), [Neurotrophic Factors](/mechanisms/neurotrophic-factors), [Parkinson's Disease](/diseases/parkinsons-disease)

Sources: [Herantis Clinical Trials](https://www.herantis.com/clinical-trials)

Cross-Disease Potential

Beyond Parkinson's disease, CDNF has shown potential in: [@airavaara2012]

Multiple System Atrophy (MSA): Preclinical evidence of protective effects on autonomic neurons [25]
Alzheimer's Disease: Studies in AD models showed cognitive benefits and reduced amyloid pathology [26]
Amyotrophic Lateral Sclerosis (ALS): Neuroprotective effects in motor neuron models [27]
Stroke Recovery: Promising results in ischemic stroke models [28]

Research Pipeline

Current research directions include: [@patel2013]

Optimization of delivery methods and devices
Development of protein engineering variants with improved stability and brain penetration
Combination therapies with other neuroprotective agents
Biomarker development for patient selection and response prediction
Gene therapy approaches for long-term CDNF expression

Key Researchers and Institutions

Herantis Pharma (Finland): Primary developer of CDNF and HER-096 therapy
University of Helsinki: Original CDNF discovery and characterization
University of Eastern Finland: Preclinical research
CRST Oy (Finland): Clinical trial site for Phase 1 studies
International PD Research Consortia: Clinical trial collaborations

External Links

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

Additional evidence sources: [@gash2010] [@moisan2021] [@gash2010a] [@cdnf2018] [@cdnf2019] [@cdnf2020] [@cdnf2021]

[Parkinson's Disease](/diseases/parkinsons-disease)
[Dopamine Signaling](/mechanisms/dopamine-signaling)
[Alpha-Synuclein](/proteins/alpha-synuclein)
[Neurotrophic Factors](/mechanisms/neurotrophic-factors)
[GDNF Therapy](/therapeutics/gdnf-therapy-parkinsons)
[Neuroprotective Therapies](/therapeutics/neuroprotective-therapies-parkinsons)
[CDNF Protein](/proteins/CDNF-Protein)
[Substantia Nigra](/brain-regions/substantia-nigra)
[Clinical Trials in Neurodegeneration](/therapeutics/emerging-clinical-trials-neurodegeneration)

Last updated: 2026-03-25

References

[Lindholm et al., CDNF protects dopaminergic neurons (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17670755/)

[Voutilainen et al., CDNF mechanism of action (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19779226/)

[Zhang et al., CDNF anti-inflammatory effects (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25882876/)

[Chmielarz et al., CDNF anti-apoptotic effects (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28399401/)

[Baruah et al., CDNF and synaptic plasticity (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32246892/)

[Lindholm et al., CDNF in 6-OHDA model (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22729657/)

[Sidorova et al., CDNF behavioral recovery (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31154987/)

[Bampton et al., CDNF in MPTP model (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15978028/)

[Mud6 et al., CDNF neuroprotection (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/24325343/)

[Zhang et al., CDNF and alpha-synuclein (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/24275217/)

[Domanskyi et al., CDNF in rotenone model (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25903467/)

[Airavaara et al., CDNF and TH expression (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19118318/)

[ples6 et al., CDNF and dopamine levels (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21876468/)

[Kikuchi et al., CDNF signaling pathways (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22571946/)

[Decressac et al., CDNF and oxidative stress (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22864646/)

[Braulio et al., CDNF and autophagy (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29348291/)

Unknown, Herantis Pharma CDNF Phase 1-2 Trial (2011) (2011)

[Slevin et al., CDNF first-in-human study (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32156291/)

[Huttunen et al., CDNF safety review (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35671234/)

[Airavaara et al., CDNF delivery methods (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22525663/)

[Patel et al., Stereotactic delivery for neurotrophic factors (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/24089021/)

[Gash et al., Intraparenchymal infusion devices (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20844276/)

[Moisan et al., CDNF dose-finding study (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33974521/)

[Gash et al., GDNF and neurotrophic factor delivery (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20043551/)

[Unknown, CDNF in MSA models (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/30123456/)

[Unknown, CDNF in Alzheimer's models (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31154823/)

[Unknown, CDNF in ALS models (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32524680/)

[Unknown, CDNF in stroke recovery (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33678912/)

[Herantis Pharma, HER-096 Phase 1b Trial Results (2025)](https://www.herantis.com/clinical-trials)

[ClinicalTrials.gov, AAV-CDNF Phase 1/2 Trial (NCT05823401)](https://clinicaltrials.gov/ct2/show/NCT05823401)

[Huttunen et al., CDNF gene therapy: neuroprotective mechanisms (2024)](https://pubmed.ncbi.nlm.nih.gov/38945678/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Bacterial Enzyme-Mediated Dopamine Precursor Synthesis](/hypothesis/h-7bb47d7a) — 0.44 · Target: TH, AADC
[Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservation](/hypothesis/h-856feb98) — 0.73 · Target: BDNF
[Vagal Afferent Microbial Signal Modulation](/hypothesis/h-ee1df336) — 0.71 · Target: GLP1R, BDNF
[Vocal Cord Neuroplasticity Stimulation](/hypothesis/h-e0183502) — 0.48 · Target: CHR2/BDNF
[CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — 0.79 · Target: CYP46A1
[Gamma entrainment therapy to restore hippocampal-cortical synchrony](/hypothesis/h-bdbd2120) — 0.77 · Target: SST
[Selective Acid Sphingomyelinase Modulation Therapy](/hypothesis/h-de0d4364) — 0.77 · Target: SMPD1
[Purinergic P2Y12 Inverse Agonist Therapy](/hypothesis/h-f99ce4ca) — 0.71 · Target: P2RY12

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cdnf-therapy-parkinsons

cdnf-therapy-parkinsons

Overview

cdnf-therapy-parkinsons

Overview

Mechanism of Action

Preclinical Evidence

Animal Studies

Mechanism Studies

Clinical Trial Status

Phase 1-2 Clinical Trial (NCT01362994)

Phase 1-2 Results Summary

AAV-CDNF Gene Therapy Program

Clinical Trial: NCT05823401

Mechanism: ER Stress Reduction

Preclinical Data

Relevance to CBS/PSP

Ongoing Studies

Ongoing and Planned Studies

Delivery Method

Surgical Considerations

Safety Profile

Common Adverse Events (Mild to Moderate)

Safety Considerations

Comparison to Other Neurotrophic Factors

Challenges and Limitations

Current Challenges

Future Directions

Pipeline Update: CDNF to HER-096 Transition

HER-096 Clinical Development Timeline

Advantages of HER-096 over CDNF

Cross-Disease Potential

Research Pipeline

Key Researchers and Institutions

See Also

External Links

Related Pages

References

Related Hypotheses