GDNF Gene Therapy for Multiple System Atrophy

Recruiting at 7 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Brain Neurotherapy Bio, Inc.

Must be taking: Anti-parkinsonian

Disqualifiers: Parkinson's, Dementia, Psychosis, Cancer, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new gene therapy for people with Multiple System Atrophy (MSA). The therapy uses a harmless virus to deliver a gene into the brain, which then produces a protein that helps protect brain cells. The goal is to see if this treatment is safe and if it can help slow down the progression of MSA.

Will I have to stop taking my current medications?

The trial requires participants to have a stable anti-parkinsonian medication regimen, so you will not need to stop taking your current medications if they are stable.

What data supports the effectiveness of the GDNF gene therapy treatment for Multiple System Atrophy?

Research on GDNF gene therapy in animal models of Parkinson's disease shows that it can increase dopamine activity and improve symptoms without adverse effects, suggesting potential benefits for similar neurodegenerative conditions. ^{1 2 3 4 5}

Is GDNF gene therapy generally safe for humans?

Research on GDNF gene therapy, including studies on animals, suggests it has a promising safety profile with no systemic toxicity observed. However, some local effects at the injection site were noted, and significant weight loss was observed in certain cases, indicating the need for careful monitoring in humans. ^{1 2 4 6 7}

How is the GDNF gene therapy treatment different from other treatments for multiple system atrophy?

The GDNF gene therapy treatment is unique because it uses a viral vector to deliver the GDNF gene directly to the brain, aiming for long-term expression of a protein that supports neuron growth and survival. This approach is different from traditional treatments as it targets the root cause of neurodegeneration rather than just alleviating symptoms. ^{1 2 3 4 8}

Eligibility Criteria

Adults aged 35-75 with Multiple System Atrophy (MSA) and parkinsonian symptoms, who can walk independently or with help. They must be diagnosed within the last 4 years, have a life expectancy over 3 years, and be on stable medication for MSA. Excluded are those with Parkinson's disease, dementia, psychosis, substance abuse issues, prior brain surgery or cancer.

Inclusion Criteria

I was diagnosed with MSA parkinsonism less than 5 years ago and expect to live more than 3 years.

My Parkinson's medication dose has been stable.

I am between 35 and 75 years old.

Exclusion Criteria

You have severe memory problems, hallucinations, drug addiction, or uncontrolled sadness.

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

I have Parkinson's disease or a related genetic condition.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AAV2-GDNF or placebo delivered to the putamen

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• AAV2-GDNF gene therapy (Gene Therapy)
• Sham (Placebo) Surgery (Procedure)

Trial Overview This study tests AAV2-GDNF gene therapy versus a sham surgery to see if it's safe and effective for treating MSA. Participants will randomly receive either the real treatment directly into their brains or a placebo procedure without knowing which one they got.

Participant Groups

Group I: Active Treatment Experimental Treatment 1 Intervention

Group II: Placebo Surgery Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Brain Neurotherapy Bio, Inc.

Lead Sponsor

Trials

2

Recruited

20+

Findings from Research

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]

GDNF (Glial cell line-derived neurotrophic factor) has shown promise in animal models for treating neurodegenerative diseases like Parkinson's disease and ALS, indicating its potential as a neuroprotective agent.

Gene therapy using viral vectors to deliver the GDNF gene directly to the central nervous system has been effective in rat models, suggesting a viable path for chronic treatment in humans, although further developments are needed for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy. Bohn, MC.[2019]

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]

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]

The developed AAV vector allows for precise control of GDNF expression in the brain, enabling up to a 300-fold increase over natural levels, with the ability to completely revert to baseline within 3-4 weeks, making it a reversible gene therapy option.

In models of Huntington's and Parkinson's diseases, this vector demonstrated effective restoration of motor functions, highlighting its potential therapeutic benefits while being free of non-induced background expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free "GeneSwitch" vector. Cheng, S., Tereshchenko, J., Zimmer, V., et al.[2019]

A systematic review of adeno-associated virus (AAV) gene therapies highlights their potential efficacy in treating previously untreatable neurological conditions, with an increasing number of clinical trials underway.

However, there are significant safety concerns, including reports of severe adverse reactions and even deaths, emphasizing the need for unified reporting of these events to enhance treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment. Horton, RH., Saade, D., Markati, T., et al.[2022]

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]

References

1. 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]

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy. [2019]

4. 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]

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

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

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

Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free "GeneSwitch" vector. [2019]

7. England pubmed.ncbi.nlm.nih.gov

A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment. [2022]

8. 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]