GDNF Gene Therapy for Parkinson's Disease

Recruiting at 2 trial locations

Overseen By Amber Van Laar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Brain Neurotherapy Bio, Inc.

Must be taking: Levodopa

Disqualifiers: Atypical parkinsonism, Dementia, Psychosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 18 months

11 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The objective of this Phase 1b investigation is to evaluate the safety and potential clinical effect of AAV2-GDNF delivered to the putamen in subjects with either a recent or a long-standing diagnosis of PD.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that participants should be responsive to levodopa, which suggests that continuing this medication might be allowed.

Is GDNF gene therapy safe for humans?

Research on GDNF gene therapy, including studies on animals and related treatments in humans, suggests it is generally safe. In animal studies, no systemic toxicity was observed, though some local effects at the injection site were noted. In human studies with a similar treatment, no serious adverse events were directly linked to the therapy, supporting its long-term safety. ^{1 2 3 4 5}

How is the AAV2-GDNF treatment for Parkinson's disease different from other treatments?

AAV2-GDNF is unique because it uses a viral vector to deliver a gene directly into the brain, which then produces a protein called GDNF that helps protect and repair brain cells affected by Parkinson's disease. This approach aims for long-term effects by targeting specific brain regions, unlike traditional treatments that often require frequent dosing and primarily manage symptoms. ^{1 4 6 7 8}

What data supports the effectiveness of the treatment AAV2-GDNF, AB-1005 for Parkinson's Disease?

Research shows that delivering GDNF (a protein that helps protect and repair brain cells) using viral vectors like AAV2 can help restore dopamine function and improve movement in animal models of Parkinson's Disease. This suggests potential benefits for patients, although clinical trials have not yet shown significant success in humans. ^{2 4 9 10 11}

Are You a Good Fit for This Trial?

This trial is for adults aged 35-75 with Parkinson's Disease (PD), diagnosed within the last 5 years with mild to moderate symptoms or at least 4 years ago with moderate to severe symptoms. Participants must respond to levodopa treatment, not have atypical parkinsonism, severe dyskinesia, dementia, psychosis, substance abuse issues or severe depression. They can't have had prior brain surgery or be on investigational drugs.

Inclusion Criteria

I was diagnosed with Parkinson's disease over 4 years ago and have moderate to severe symptoms.

I was diagnosed with Parkinson's disease recently.

I am between 35 and 75 years old.

Exclusion Criteria

I experience severe involuntary movements.

I have a history of cancer or medical conditions that could make surgery risky.

Currently taking a medication that is still being tested and not approved for general use.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AAV2-GDNF gene therapy delivered to the putamen

18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• AAV2-GDNF

Trial Overview The study tests AAV2-GDNF gene therapy delivered to a part of the brain called putamen in people with PD. It aims to assess safety and potential benefits of this treatment for those newly diagnosed or living long-term with PD.

How Is the Trial Designed?

Group I: Later stage PD Experimental Treatment 1 Intervention

Group II: Earlier stage PD Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Brain Neurotherapy Bio, Inc.

Lead Sponsor

Trials

2

Recruited

20+

AskBio Inc

Industry Sponsor

Trials

8

Recruited

440+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Asklepios Biopharmaceutical, Inc.

Industry Sponsor

Trials

8

Recruited

440+

Published Research Related to This Trial

Glial cell line-derived neurotrophic factor (GDNF) shows promise in protecting and regenerating dopamine neurons in animal models of Parkinson's disease, suggesting it could be a potential treatment for preserving and restoring function in patients.

Gene therapy using encapsulated, GDNF-secreting cells offers a novel approach for delivering GDNF, with the added safety feature of being able to remove the cells if adverse effects occur, paving the way for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encapsulated cell biodelivery of GDNF: a novel clinical strategy for neuroprotection and neuroregeneration in Parkinson's disease? Lindvall, O., Wahlberg, LU.[2008]

In a study using a rat model of Parkinson's disease, administering rAAV-GDNF after a significant neurotoxic lesion led to notable behavioral recovery and increased dopaminergic markers within 4 weeks, indicating its potential efficacy in restoring dopamine function.

This research suggests that rAAV-GDNF gene therapy could effectively rescue dopaminergic neurons and improve motor function in conditions that closely mimic advanced Parkinson's disease, highlighting its therapeutic promise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated viral delivery of GDNF promotes recovery of dopaminergic phenotype following a unilateral 6-hydroxydopamine lesion. McGrath, J., Lintz, E., Hoffer, BJ., et al.[2019]

Recombinant viral vectors, specifically AAV and LV, have been shown to effectively deliver glial cell line-derived neurotrophic factor (GDNF) in rat models of Parkinson's disease, preventing degeneration of dopamine neurons and preserving striatal function.

Long-term delivery of GDNF using these vectors over 3-6 months resulted in significant functional recovery in both rats and monkeys, indicating their potential for neuroprotective treatments in human patients with Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Björklund, A., Kirik, D., Rosenblad, C., et al.[2022]

Direct gene delivery of AAV2-glial-derived neurotrophic factor (GDNF) to the brain shows promise for treating Parkinson's disease, with successful transport and expression observed in key brain regions after targeted delivery.

Using real-time image-guided techniques improved the accuracy of gene transfer, which is crucial since previous trials failed due to insufficient coverage of the target area, highlighting the importance of delivery methods in achieving therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glial-derived neurotrophic factor gene transfer for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain. Kells, AP., Forsayeth, J., Bankiewicz, KS.[2021]

The study assessed the safety of AAV2-human GDNF in rats, finding no systemic toxicity and only reversible local toxicity at the injection site, indicating a promising safety profile for this treatment in Parkinson's disease models.

The lowest dose of 6.8 × 108 vector genomes per dose was identified as the no observed adverse effect level, suggesting it may be the safest option for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease. Terse, PS., Kells, AP., Noker, P., et al.[2022]

A long-term safety assessment of rAAV2-neurturin in 53 patients with advanced Parkinson's disease showed that the treatment is generally safe, with only a few non-serious adverse events reported, none of which were definitively linked to the therapy.

Over a follow-up period of up to 5 years, patients demonstrated stable or modestly improved motor function, indicating that rAAV2-neurturin not only has a favorable safety profile but may also provide therapeutic benefits in managing Parkinson's disease symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Safety of Patients with Parkinson's Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer. Marks, WJ., Baumann, TL., Bartus, RT.[2022]

In a study involving 17 aged rhesus macaques, the administration of AAV2-GDNF into the substantia nigra resulted in a significant weight loss of 19.4%, raising safety concerns for this method of treatment.

Conversely, in a separate study with 11 MPTP-lesioned macaques, AAV2-GDNF delivery to the putamen did not cause weight loss and showed potential therapeutic benefits, indicating that the method may be safer when targeting the putamen rather than the substantia nigra.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Su, X., Kells, AP., Huang, EJ., et al.[2021]

AAV2-GDNF gene therapy safely delivers therapeutic levels of glial cell-derived neurotrophic factor (GDNF) to targeted brain areas in aged nonhuman primates, enhancing dopaminergic innervation without significant adverse effects.

High-dose AAV2-GDNF treatment increased the density of dopaminergic terminals and improved dopamine turnover in the putamen, suggesting potential benefits for restoring dopaminergic function in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. Johnston, LC., Eberling, J., Pivirotto, P., et al.[2021]

AAV2 viral vectors have been developed to deliver neurotrophic factors like NGF and NRTN, showing promising results in animal studies with sustained protein expression and no safety issues, paving the way for clinical applications in Alzheimer's and Parkinson's diseases.

These vectors have successfully advanced into multi-center, double-blind clinical trials, indicating their potential to address long-standing delivery challenges associated with neurotrophic factors in treating neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. Herzog, CD., Bishop, KM., Brown, L., et al.[2018]

In a study using a primate model of Parkinson's disease, the infusion of an adeno-associated virus (AAV2) carrying human GDNF significantly increased dopaminergic activity in the brain, as shown by enhanced FMT uptake six months post-treatment.

The AAV2-GDNF treatment not only improved clinical symptoms in the primates but also demonstrated a good safety profile, with no adverse effects observed during the six-month follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. Eberling, JL., Kells, AP., Pivirotto, P., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Encapsulated cell biodelivery of GDNF: a novel clinical strategy for neuroprotection and neuroregeneration in Parkinson's disease? [2008]

2. United States pubmed.ncbi.nlm.nih.gov

Adeno-associated viral delivery of GDNF promotes recovery of dopaminergic phenotype following a unilateral 6-hydroxydopamine lesion. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Glial-derived neurotrophic factor gene transfer for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Gene therapy for Parkinson's disease: Disease modification by GDNF family of ligands. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Long-Term Safety of Patients with Parkinson's Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. [2021]