GDNF Gene Therapy for Multiple System Atrophy

Not currently recruiting at 7 trial locations

Overseen By David Charles, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Brain Neurotherapy Bio, Inc.

Must be taking: Anti-parkinsonian

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, AAV2-GDNF, for individuals with Multiple System Atrophy (MSA), a progressive condition affecting movement and balance. The goal is to determine the treatment's safety and potential to manage symptoms. Participants will either receive the gene therapy or undergo a placebo surgery for comparison. Eligible participants must have been diagnosed with the parkinsonian type of MSA within the last five years and be able to walk 25 feet, even with assistance. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that AAV2-GDNF gene therapy is currently being tested for human safety. This therapy delivers a specific gene to the putamen, a part of the brain. The primary goal is to assess its safety for individuals with Multiple System Atrophy, a rare brain disorder.

As an early phase study, scientists are beginning to examine its effects in humans. At this stage, limited information exists on how well people tolerate it or what side effects may occur.

Clear data on reactions to this treatment is not yet available. However, the studies aim to ensure safety before evaluating effectiveness. So far, the available information has reported no major safety concerns. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Multiple System Atrophy (MSA) focus on managing symptoms, but AAV2-GDNF gene therapy offers a different approach. This treatment is unique because it uses a viral vector to deliver the GDNF gene directly into brain cells. GDNF, or glial cell line-derived neurotrophic factor, has the potential to protect and repair neurons, addressing the root cause of neurodegeneration rather than just alleviating symptoms. Researchers are excited about this therapy because it could slow or even halt disease progression, which current treatments cannot achieve.

What evidence suggests that AAV2-GDNF gene therapy might be an effective treatment for Multiple System Atrophy?

Research has shown that AAV2-GDNF gene therapy, a treatment available to participants in this trial, might benefit individuals with Multiple System Atrophy (MSA). In studies on Parkinson's disease, this therapy demonstrated promising results over a 36-month period, with participants experiencing some symptom improvements. The therapy delivers a protein called GDNF, which supports nerve cells, directly to the brain. Early studies suggest this method is safe and could be effective, but further research is needed to confirm these findings specifically for MSA. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• AAV2-GDNF gene therapy
• Sham (Placebo) Surgery

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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