Alisa G. Woods, PhD

Danish and German scientists have identified impaired cytokine interferon-Î² (IFN-Î²) signaling as a possible molecular trigger for Parkinson disease dementia, as well as the related neurodegenerative disorder, Lewy body dementia. Correcting deficits in IFN-Î² via gene therapy may one day provide a treatment for these neurodegenerative diseases.

Parkinson disease is characterized by tremor and rigidity, caused by loss of basal ganglia dopaminergic neurons and marked by the presence of Lewy bodies-aggregated protein deposits containing alpha-synuclein. Dementia is another characteristic of later stages of the disease. Lewy body dementia shares overlapping characteristics with Parkinson disease. The two disorders are more distinct in earlier stages, since Parkinson is characterized by movement symptoms initially, while dementia occurs earlier in Lewy body disease.

The research report appeared in the prestigious journal 

. According to the study, IFN-Î² is responsible for neuronal homeostasis and cellular clean-up, and the absence of the cytokine could trigger neurodegenerative disease.

Led by Patrick Ejlerskov of the University of Copenhagen, the researchers studied mice that lacked IFN- Î², known as 

 mutant mice. The animals had impairments in both cognitive function and in movement, as measured by a water maze and RotaRod test, both standard behavioral tasks. The scientists used immunostaining of the mouse brain to identify the presence of Lewy bodies in the brain containing the characteristic protein alpha-synuclein. Surprisingly, they also found a reduction in dopamine neurons in the substantia nigra as well as impaired dopamine neuronal signaling-hallmark signs of Parkinson disease.

According to the study authors, the alpha-synuclein and Lewy body accumulation are the consequence of “late-stage autophagy.” Autophagy is a mechanism for cleaning up the cell. The process degrades proteins, organelles, lipids, and aggregates of protein and is a critical homeostatic process for the neuron.

“We found that IFN-Î² is essential for neurons’ ability to recycle waste proteins. Without this, the waste proteins accumulate in disease-associated structures called Lewy bodies and with time the neurons die,” noted Ejlerskov in a press release.

As a final stage of the study, the scientists tested the effects of corrective gene therapy in a rat model of Parkinson disease induced by injecting human alpha-synuclein into the rat substantia nigra. They used a lentivirus to over-express IFN-Î² in one group of the Parkinsonian  rats while another control group received the lentivirus only, as a sham treatment. The animals without the corrective gene therapy developed problems with autophagy and accumulation of several proteins in the brain, including alpha-synuclein. The animals with IFN-Î² overexpression did not have these problems. The gene therapy also protected dopamine neurons in the substantia nigra and improved movement problems in the animals. The scientists concluded in their manuscript “We showed that Ifnb gene therapy reversed pathology in a familial PD model, by promoting autophagy and a-syn clearance, which preserved DA neurons and associated neurologic deficit.”

Not only did this research study identify a possible new animal model for Parkinson disease and Lewy body dementia, but it the results also suggest a potential new avenue for gene therapy in these neurological conditions.

In a press release, principal investgator Shohreh Issazadeh-Navikas remarked, “This is one of the first genes found to cause pathology and clinical features of non-familial PD and DLB, through accumulation of disease-causing proteins. It is independent of gene mutations known from familial PD and when we introduced IFNÎ²-gene therapy, we could prevent neuronal death and disease development. Our hope is that this knowledge will enable development of more effective treatment of PD.”

Lack of neuronal IFN-Î²-IFNAR causes Lewy body- and Parkinson’s disease-like dementia

Articles

The discovery of a possible trigger for PD and Lewy body dementia could provide a new avenue for gene therapy in these neurological conditions.

Parkinson and Lewy Body-like Dementia Triggers

Parkinson disease (PD) treatments most often target dopamine, a neurotransmitter that decreases because of the death of substantia nigra neurons. Now scientists are testing alternative approaches-gene therapy directed at increasing the growth factors neurturin (NRTN) and glial cell-derived neurotrophic factor (GDNF)-with the goal of protecting substantia nigra neurons from dying.

Therapies have not been successful yet. But many researchers think that, based on the known effects of these molecules, neurotrophic factors hold particular promise for not only delaying PD progression but possibly even protecting and regenerating neurons.

“Inherently it seems like the neurotrophic strategy may be better [than targeting dopamine deficits]…but so far they’re not showing benefits,” said geneticist Xandra Breakefield, PhD, a professor of neurology at Harvard Medical School in Boston.

For example, Ceregene’s CERE-120, a viral vector used to deliver the NRTN gene into the substantia nigra and the striatum, did not achieve clinical goals in two Phase 2 trials. However, although there were no measured benefits at the designated 12-month end point, some improvements in PD symptoms occurred later, at 15 to 18 months after the surgery.

Further development of the treatment is unclear. “All of the rights to Ceregene’s technology and programs were acquired by Sangamo in 2013,” according to Raymond Bartus, PhD, a former investigator on several neurological gene therapy trials. “Because they have publicly disclosed little information, it is not possible to discuss their intention for continued development of CERE-120.”

In another neurotrophic factor approach, at the University of California, San Francisco, neurosurgeon Krystof Bankiewicz, MD, PhD, along with John Heiss, MD, of the National Institute for Neurological Disorders and Stroke, currently are treating 24 patients with PD in a Phase 1 study examining a viral vector containing the gene for GDNF.

Dr Bankiewicz and colleagues are using MRI guidance, or “interventional MRI,” to deliver the drug.  According to Dr Bankiewicz, with use of this technique there are “so far no safety issues…we know that the drug is getting to the right place. We need to wait for the clinical data.” It only remains to be seen whether clinical efficacy is in fact improved with the additional use of MRI.

Michael Hutchinson, MD, a neurologist at Mount Sinai Hospital in New York City, is convinced that GDNF in particular has a bright future as a treatment for PD, not only to delay neural deterioration but also to protect neurons. He thinks that “GDNF is a very interesting molecule, we really think it works like gangbusters.”

Dr Hutchinson’s optimism is based largely on GDNF infusion studies. GDNF infusion into the putamen has improved movement and shown evidence of neuron regeneration in humans.

 Success for GDNF gene therapy may require the patience of researchers to optimize dosing and delivery, which may now indeed be achieved through the use of MRI.

Susan Gurney, PhD, a scientist working in the Columbia University Department of Epidemiology in New York City who worked on trials involving direct infusion of GDNF, thinks that gene therapy could be a better approach than simply infusing growth factors into the brain. She stated, “The genetic vector methods allow for a one-time surgery, with almost no risk of infection.”

Gene therapy trials targeting growth factors continue. Whether the approach will succeed and these treatments make it to clinical use remains to be seen.

Timing may be essential to PD gene therapy success, according to Francesco Roselli, MD, PhD, a physician and neurobiologist at the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. “Early correction may block the progression of the disease and allow long-term treatment by pharmacology alone,” he said.

• Gene therapy for PD involves increasing the growth factor NRTN or GDNF.

• Growth factor gene therapies have so far not been successful, possibly because of  problems with dosing.

• MRI may improve gene therapy dosing, but more data are needed.

1. Bartus RT, Baumann TL, Siffert J, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neuturin in Parkinson patients. 

2. Patel NK, Pavese N, Javed S, et al. Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation. 

Scientists are testing alternative therapeutic approaches that may delay disease progression and even protect and regenerate neurons.

Parkinson Gene Therapy Targets Growth Factors

Gene therapies for Parkinson disease (PD) appeared to be safe in clinical trials, but up until now these treatments have not produced promising efficacy results. MRI could be the key to improvement.

For more than a decade, researchers have been working on gene therapy treatments for PD. Although it may seem counterintuitive, gene therapy uses viruses that insert DNA into cells in the brain with the goal of churning out helpful molecules.

Therapeutic targets have included increasing dopamine levels to help balance out PD dopamine deficits and increasing gamma amino butyric acid (GABA), an inhibitory neurotransmitter that can quell brain regions overactive in PD. Researchers also have attempted to boost levels of protective growth factors, such as glial-derived neurotrophic factor (GDNF) and neurturin (NRTN), to potentially protect and regenerate susceptible neurons.

The good news is that these therapies now appear to be safe. However, efficacy results so far have been disappointing. For example, phase 2 studies of NLX-P101, a gene therapy designed to boost GABA levels,

 gene therapy to increase NRTN, showed only limited movement improvements. Similarly, two Phase 1 trials that studied aromatic-L-amino acid decarboxylase (AADC) gene therapy, designed to increase levels of dopamine, showed only modest efficacy.

Neurosurgeon Krystof Bankiewicz, MD, PhD, of the University of California, San Francisco, is a leading investigator in the development of the AADC gene therapy.

 “The issue that was identified is that we were not able to have adequate coverage with the brain therapy…the needle was placed inside the brain without us knowing if the needle was placed correctly,” he told Neurology Times.

Despite setbacks, gene therapy research for PD pushes forward, this time with the help of MRI to guide where the infusion goes during surgery. Dr Bankiewicz suggested that the key is placement of the injections used in gene therapy, as well as using an appropriate volume of the viral vectors. He stated, “I think all the gene therapy trials never really touched the potential simply because the drug was not delivered correctly.”

Dr Bankiewicz and colleagues are continuing trials of AADC-containing viral vectors, as well as GDNF-containing viral vectors, using MRI to direct drug placement, spiked with a gadolinium tracer that shows where the infusion has gone on the MRI scan.

Dr Bankiewicz is optimistic about the potential of these studies, stating, “Because of the image-guided delivery we are very pleased with having a planned delivery.”

• Gene therapies for PD are safe, but studies have not produced convincing findings about efficacy.

• MRI could direct placement of PD gene therapies.

• Trials of PD gene therapy, using MRI to guide placement, are under way.

1. Bartus RT, Weinberg MS, Samulski RJ. Parkinson’s disease gene therapy: success by design meets failure by efficacy. 

2. Diaz-Nido J. NLX-P101 an adeno-associated virus gene therapy encoding glutamic acid decarboxylase, for the potential treatment of Parkinson’s disease. 

3. Bartus RT, Baumann TL, Siffert J, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neuturin in a Parkinson patients. 

4. Muramatsu S, Fujimoto K, Kato S, et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. 

5. Eberling JL, Jagust WJ, Christine CW, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. 

Up until now, these treatments have not produced promising efficacy results in clinical trials. MRI could show the way.

Alisa G. Woods, PhD

Articles

Parkinson and Lewy Body-like Dementia Triggers

Parkinson Gene Therapy Targets Growth Factors

MRI May Advance Parkinson Gene Therapy