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One-year Results in 2 Given Gene Therapy at Low Dose Showing Promise, Axovant Reports

early trial results

Two Parkinson’s patients treated with AXO-Lenti-PD, an investigative gene therapy, in an ongoing clinical trial continue to show improvement 12 months later, Axovant, the therapy’s developer, said in a release.

These findings at one year after treatment are important because this timepoint allows for a better assessment of therapy durability, and a more assured differentiation between placebo effects and therapeutic response, the company added.

AXO-Lenti-PD has shown encouraging results in these two people given a first low dose in the SUNRISE-PD (NCT03720418) Phase 1/2 clinical trial, which is now enrolling up to 30 patients at sites in France and England.

The treatment works by delivering three genes involved in dopamine production directly to the brain via a surgical procedure.

Dopamine is a neurotransmitter — a molecule involved in transmitting information between neurons — that is critical to coordinating movement. Dopamine-producing (dopaminergic) neurons are lost in Parkinson’s, and the resulting drop in dopamine levels is the cause of many disease symptoms.

By ‘infecting’ brain cells with the genetic instructions to increase dopamine production, AXO-Lenti-PD aims to turn other cells into dopaminergic neurons.

Current dopamine replacement therapies require continual oral doses of dopamine, whose effectiveness fades over time. The period between when one dose’s effectiveness wanes and the taking of a next dose can result in “off periods,” wherein patients report a return of symptoms such as poor motor control, stiffness, fatigue and mood changes.

Helping the brain to again produce adequate levels of dopamine would, in theory, eliminate the need for periodic oral doses, which could significantly limit off periods.

Previous studies in primate models of Parkinson’s found AXO-Lenti-PD to be safe and effective, and SUNRISE-PD results at three months’ post-treatment found that a one-time delivery of the therapy significantly improved patient scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), a standard assessment of motor and non-motor symptoms associated with Parkinson’s.

The trial consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of potentially three escalating doses of the gene therapy. In part B, a new group of patients will be randomized to either the ideal part A dose or to a sham procedure as an untreated control group. SUNRISE-PD’s goal is to test the safety, tolerability, and effectiveness of the potential treatment.

Both patients here, the first two enrolled, received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD.

One-year results show positive changes of 24 points and 20 points (respectively for the two patients) on the UPDRS Part III “Off” score, representing a 37% improvement in off-period motor symptoms, Axovant reported. Improvement at six months was 29%, as measured on the same scale.

These patients also showed an average 13-point positive change from baseline (study start) — representing a 44% improvement — on the UPDRS Part II “Off” score, which assesses daily life activities. On the PDQ-39 score index, another quality-of-life measure in Parkinson’s disease, these two showed an average 15-point positive change, or a 30% improvement from baseline to 12 months.

Both patients tolerated AXO-Lenti-PD well, and neither reported any serious side effects. One maintained a diary of on/off periods, which is useful in evaluating changes that might be due to therapy across time.

People being enrolled in SUNRISE-PD have had Parkinson’s for at least five years, have motor fluctuations and dyskinesia (jerky, involuntary movements), and are between the ages of 48 and 70.  More information can be found here.

The company expects to soon release six-month results on the first two patients given a second and higher dose of AXO-Lenti-PD. This dose is three times higher than that given the first cohort.

If dose-escalation results allow, Axovant expects to begin the randomized and placebo-controlled part B of the SUNRISE-PD as a Phase 2 study by the close of 2020.

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New Gene Therapy Delivery Method May Open BRAVE New World in Parkinson’s Research

BRAVE gene therapy method

A new method allows researchers to develop adeno-associated virus (AVV) — commonly used as the vehicle for gene therapies — that accurately target and deliver genes to specific cells in the body.

This new technology may be suitable to target dopaminergic neurons that are damaged in Parkinson’s disease.

“We believe that the new synthetic [lab-made] virus we succeeded in creating would be very well suited for gene therapy for Parkinson’s disease, for example, and we have high hopes that these virus vectors will be able to be put into clinical use,” Tomas Björklund, PhD, Lund University, Sweden, said in a press release.

Björklund is lead author of the study “A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism,” which was published in the journal Proceedings of the National Academy of Sciences. 

The adeno-associated virus (AAV) is a common, naturally-occurring virus, which has been shown to work as an effective gene therapy delivery vehicle for genetic diseases, such as spinal muscular atrophy. In gene therapy, scientists deliver a working version of a faulty gene using a harmless AAV that was modified and inactivated in the lab. This way the virus functions only as a delivery vehicle and does not have the capacity to damage tissues and cause disease.

While AAVs have a natural ability to penetrate any cell of the body and infect as many cells as possible, their usefulness as a potential therapy requires the capacity to specifically deliver a working gene to a particular cell type, such as dopamine producing-nerve cells. Those are the ones hose responsible for releasing the neurotransmitter dopamine and that are gradually lost during Parkinson’s disease.

A team of Swedish researchers have developed a new method — called barcoded rational AAV vector evolution, or BRAVE — that combines powerful computational analysis with the latest gene and sequencing technology to produce AAVs that can specifically target neurons.

To make AAVs neuron specific, the team selected 131 proteins known to specifically interact with synapses (the junctions between two nerve cells that allow them to communicate).

They then divided the proteins into small sequences, called peptides, and created a large library where each peptide could be identified by a specific pool of genetic barcodes (a short sequence of DNA that is unique and easily identified).

The peptide is then displayed on the surface of the AAV capsid, allowing researchers to test the simultaneous delivery of many cell-specific AAVs in a single experiment.

The team then injected these AAVs into the forebrain of adult rats and observed that around 13% of the peptides successfully homed to the brain. Moreover, 4% of the peptides were transported effectively through axons (long neuronal projections that conduct electrical impulses) toward the nerve cell’s body.

Researchers then selected 23 of these unique AAV capsids and injected them into rats’ striatum, a brain region involved in voluntary movement control and affected in Parkinson’s disease. Twenty-one of the new AAV capsids had an improved transport capacity within nerve cells than in standard AAVs.

One particular capsid, called MNM008, showed a high affinity for rat dopaminergic neurons. Researchers then tested whether this viral vector also could target human dopaminergic neurons.

The team transplanted neurons generated from human embryonic stem cells into rats’ striatum. Six months later, they injected either MNM008 or a control AAV capsid and found that MNM008 was able to target these specific cells and be transported into dopaminergic neuronal cell bodies through axons.

“Thanks to this technology, we can study millions of new virus variants in cell culture and animal models simultaneously. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen application — in this case, the dopamine-producing nerve cells for the treatment of Parkinson’s disease,” Björklund said.

Overall, researchers believe the BRAVE method “opens up the design and development of synthetic AAV vectors expressing capsid structures with unique properties and broad potential for clinical applications and brain connectivity studies.”

The team has established a collaboration with a biotech company, Dyno Therapeutics, to use the BRAVE method in the design of new AAVs.

“Together with researchers at Harvard University, we have established a new biotechnology company in Boston, Dyno Therapeutics, to further develop the virus engineering technology, using artificial intelligence, for future treatments,” Björklund said.

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Phase 2 Trial of Gene Therapy, VY-AADC02, for Advanced Parkinson’s Enrolling in US

VY-AADC02 trial

A Phase 2 clinical trial testing the safety and effectiveness of the gene therapy VY-AADC02 in people with advanced Parkinson’s disease is recruiting patients at select sites across the U.S., according to a release by one such site.

Hackensack University Medical Center is among the 17 institutions across the U.S. enrolling up to 40 patients ages 40 to 75 , all diagnosed four or more years ago, for the double-blinded RESTORE-1 (NCT03562494) study.

Eligible patients must be experiencing unpredictable motor fluctuations despite use of treatments, and are not planning to undergo neurological surgeries such as deep brain stimulation or take new dopaminergic formulations during the study.

An eligibility questionnaire is available on the trial’s website.  Contact information for participating sites can also be found here.

RESTORE-1 will assess the safety and efficacy of VY-AADC02, delivered in a surgical procedure monitored in real-time via magnetic resonance imaging. Treatment with the gene therapy will be compared to a “sham” procedure, with half of the enrolled patients randomly assigned to treatment.

Trial participants must be able to make at least 21 visits to their clinical site, spread over two months of pre-treatment assessments and 12 months of follow-up.

Parkinson’s is characterized by progressive loss of dopamine-producing nerve cells and lower levels of the L-amino acid decarboxylase (AADC) enzyme, which mediates the conversion of levodopa into dopamine.

VY-AADC02 is a gene therapy developed by Neurocrine Biosciences and Voyager Therapeutics. It uses a modified, harmless viral vector to deliver the AADC gene directly into the putamen, a brain region associated with motor control and filled with dopamine receptors. This gene carries the information for the production of the AADC enzyme.

Latest results of the Phase 1 PD-1102 clinical trial (NCT03065192) found that treatment with VY-AAD01 — a precursor of VY-AADC02 — into the striatum (a brain area that includes the putamen) improved motor function and reduced the need for antiparkinsonian medications by 28% in patients with advanced Parkinson’s.

Other benefits included an 85% increase in AADC activity in the putamen, and improvements in a quality of life score.

A Phase 1b trial in that precursor therapy, called PD-1101 (NCT01973543), has shown dose-dependent improvements in motor function and quality of life, as well as a reduced need for antiparkinsonian medications.

These two studies use different surgical approaches. In PD-1101, the gene therapy was injected through the top of the head (called a frontal approach), and in PD-1102 it was delivered through the back (a posterior approach), which is intended to both reduce the infusion time and increase the therapy’s coverage of its targeted brain area.

Participants who complete trials of either VY-AADC01 or VY-AADC02 will have the possibility of joining a long-term extension study (NCT03733496), expected to conclude in August 2026.

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Early Trial for Prevail’s One-time Gene Therapy PR001 to Start Soon

PR001 GBA1 trial

Prevail Therapeutics will soon start its Phase 1/2 clinical trial evaluating the safety, tolerability, and early efficacy of its one-time gene therapy — called PR001 — for Parkinson’s disease associated with mutations in the GBA1 gene.

The trial is expected to enroll up to 16 people with confirmed GBA1 mutations. Participants will be randomly assigned to receive two escalating doses of PR001, or placebo, administered as a single injection.

The company expects that dosing will start during 2019.

“We are excited to begin dosing patients in our Phase 1/2 clinical trial for PD-GBA this year,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release. “We believe PR001 has tremendous potential to slow or stop disease progression in patients with PD-GBA … who currently have no disease-modifying therapeutic options.”

People with GBA1 mutations have up to a five-fold higher risk of developing Parkinson’s disease. Indeed, estimates point to a link to GBA1 mutations in 7 to 10% of all Parkinson’s cases.

The GBA1 gene contains all the information necessary to produce the enzyme beta-glucocerebrosidase (GCase) — an important component of cells’ recycling factories, called lysosomes. Lack of this enzyme, or its faulty activity, will make cells accumulate toxic substances inside them, which may contribute to the neurodegeneration seen in Parkinson’s disease.

PR001 was designed as a single-dose gene therapy that will provide nerve cells with a fully working copy of the GBA1 gene. This new method uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver the gene to cells, which will then be able to recover GCase function.

This gene therapy is expected to ease Parkinson’s disease symptoms triggered by the mutated gene.

Studies in mice and primates with Parkinson’s disease demonstrated that PR001 was well-tolerated. The gene therapy also was found to promote an increase in GCase enzyme activity, which resulted in reduced accumulation of toxic fatty molecules, and improvements in motor function.

The U.S. Food and Drug Administration (FDA) granted fast track designation to PR001 in July 2019 for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations. The designation accelerates the therapy’s development and may help expedite its approval by providing more frequent meetings with the FDA and discussions about the therapy’s development plan.

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Gene Therapy in Clinical Trial, AXO-Lenti-PD, Safe And Effective in Monkey Model of Parkinson’s, Study Says

gene therapy study

The experimental gene therapy AXO-Lenti-PD (OXB-102) was seen to be both safe and effective in a primate model of Parkinson’s disease, a study reported, supporting a clinical trial getting underway in patients.

The findings were published in the journal Molecular Therapy Methods & Clinical Development in the paper, “Gene Therapy for Parkinson’s Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.”

Parkinson’s disease is caused by a lack of the neurotransmitter dopamine in the brain as a consequence of the degeneration of dopamine-producing neurons. Oral dopamine replacement therapies (e.g., levodopa) can provide symptom relief, but their benefits tend to weaken — and unpleasant side effects multiply — when used over a long period.

The idea behind gene therapy for Parkinson’s is that, rather than swallowing a pill to get more dopamine, cells in the brain could be engineered to make more on their own. One such therapy, called ProSavin, demonstrated promising results in early clinical trials — but data also suggested that this gene therapy didn’t increase dopamine production enough for maximum benefit.

Like ProSavin, AXO-Lenti-PD gene therapy takes the form of a virus that has been modified to deliver a genetic payload that lets cells make more dopamine. But for AXO-Lenti-PD, the particular coding “instructions” have been optimized to get the most dopamine production possible. The therapy is administrated surgically directly into the brain.

AXO-Lenti-PD, developed by Oxford Biomedica and Axovant, is currently being evaluated in the SUNRISE-PD (NCT03720418) Phase 1/2 clinical trial that is enrolling patients at sites in England and France. To date, a single dose of  AXO-Lenti-PD is reported to be well-tolerated and to have improved motor function after six months in two people with advanced Parkinson’s disease.

In this preclinical study, researchers induced Parkinson’s-like symptoms in macaques using a compound called MPTP. The monkeys were then treated with either a high or low dose of AXO-Lenti-PD, or with ProSavin or a control vector. (Oxford Biomedica also developed ProSavin.)

Compared to animals in the control group, those given an active gene therapy showed significantly fewer parkinsonian symptoms at three and six months post-treatment. Although there were no statistically significant differences between the three treatment groups in terms of clinical scores, animals that received the high dose of AXO-Lenti-PD had higher motor scores than the ProSavin-treated animals at three and six months post-treatment.

Furthermore, assessment of the macaques’ brains suggested that those treated with either dose of AXO-Lenti-PD produced significantly higher levels of aromatic L-amino acid decarboxylase (AADC, an enzyme that helps in the production of dopamine) than those treated with ProSavin. The highest AADC expression was found in the high-dose AXO-Lenti-PD group, suggesting that this group had the most dopamine production (although this was not directly assessed).

AXO-Lenti-PD’s use also appeared to be safe. “Over the 26-week observation period, OXB-102 was demonstrated to be well tolerated and with no clinical signs or abnormal observations noted,” the team wrote.

Researchers did note that all animals given the investigational gene therapy developed antibodies against its viral vector, which may be a concern. Antibody development means that, if the vector were to be used again, it would likely be less effective because the body would fight it.

“In conclusion,” the researchers wrote, “the results achieved in these pre-clinical studies demonstrate the efficacy and safety of an enhanced dopaminergic lentiviral vector, OXB-102, and strongly support the clinical evaluation in patients with [Parkinson’s disease].”

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Prevail’s Gene Therapy Candidate PR001 Granted FDA Fast Track Status

PR001 Fast Track

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Prevail Therapeutics’ lead gene therapy candidate, PR001, for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations.

Fast Track status will support and expedite the clinical development, regulatory review, and potential marketing approval of PR001.

The FDA’s decision follows its acceptance of Prevail’s Investigational New Drug application in June. That IND acceptance will allow the company to initiate a Phase 1/2 clinical trial to assess PR001’s safety and tolerability.

Prevail expects to launch the trial, and start dosing patients, during the second half of 2019.

“We are pleased that the FDA has granted Fast Track Designation for PR001, which underscores the unmet need of patients with Parkinson’s disease with a GBA1 mutation,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

People who carry a mutated GBA1 gene can have up to 5 times higher risk of developing Parkinson’s disease. Even though it remains unclear what links the two conditions, it is estimated that 7 to 10% of all Parkinson’s cases are related to GBA1 mutations.

The GBA1 gene holds the instructions to produce the enzyme beta-glucocerebrosidase (GCase). That enzyme is essential for the digestion and recycling of different types of molecules and cellular debris in tiny vesicles called lysosomes. If GCase activity is impaired in any way, toxic substances accumulate inside cells, particularly as people age, leading to excessive inflammation and —probably, scientists say — the neurodegeneration seen in Parkinson’s disease.

PR001 is intended to be a disease-modifying and single-dose gene therapy for individuals with mutations in the GBA1 gene. It uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver a fully working copy of the defective gene to nerve cells. This should allow for long-lasting expression of working beta-glucocerebrosidase, easing disease symptoms caused by the mutated gene.

Studies in mice and primates with Parkinson’s disease demonstrated that PR001 was well-tolerated. The gene therapy was found to promote an increase in GCase enzyme activity in mice. That resulted in reduced accumulation of fatty molecules, and improvements in motor function.

“With no treatments available that modify the progressive course or the underlying disease process of Parkinson’s disease, a potential disease-modifying therapy like PR001 could significantly transform the lives of patients with this disease,” Abeliovich said.

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Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

gene therapy study

Direct delivery of two dopamine-synthesizing enzymes to the midbrain, using a safe and inactive form of an adenovirus, was able to reverse signs of motor difficulties in a primate model of Parkinson’s disease, a study reports.

Continuous dopamine production via a gene therapy approach may be a promising one-time treatment strategy for Parkinson’s patients, providing long-lasting improvement and lowering the chances of motor fluctuations and other side effects associated with oral dopaminergic medication, its researchers suggest.

The study, “Vector-mediated L-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease,” was published in the journal Brain.

Treatment with levodopa — a precursor molecule of dopamine — remains the leading standard treatment of Parkinson’s, easing effects caused by damaged or dead dopamine-producing brain cells, the main cause of this disease.

Such treatment effectively helps to manage Parkinson’s motor symptoms, but dopamine agonists often becomes less effective over time. This is believed to be due, at least in part, to lesser production of the enzymes involved in dopamine production.

Recently researchers have focused on developing types of gene therapy that might overcome the long-term ineffectiveness of available treatments.

An international team of researchers designed a gene therapy approach to re-establish the amount of available enzymes known as TH and GCH1 — both necessary for dopamine production — in the midbrain.

Using an engineered adeno-associated viral (AAV) vector to simultaneously deliver the DNA coding sequences of the two enzymes, researchers injected different doses of the gene therapy directly into the putamen — one of the brain areas mostly affected by the disease — of 29 rhesus monkeys. Four animals were left untreated as a control group.

The putamen is also the brain region where most dopamine-producing cells are located.

One group of animals, initially given the lowest dose, was given a second and higher dose six months after a first injection to simulate “a clinical scenario where patients entering early in the safety trial could be offered a therapeutic dose at the end of the trial.” All animals were analyzed 10 months after the initial dosing.

“The re-dosed animals showed a significant recovery over the following 2 months, reaching the same level of recovery as the initial high-dose treatment group,” the study notes.

Importantly, the primates had been treated with increasing L-DOPA doses before the injection of the gene therapy, “given twice daily for 2 weeks to induce L-DOPA-induced dyskinesia,” the scientists wrote.

Findings showed that the therapy induced a significant and dose-dependent improvement in motor control up to a level similar to that obtained with the optimal dose of injectable levodopa.

Reported improvements in motor function also came without any signs of dyskinesia — the uncontrolled, involuntary movements that are often associated with long-term levodopa use.

Analysis of brain tissue samples collected from the monkeys showed that this AAV-mediated gene therapy could induce an increase of 760- to 5600-fold of TH and 1.2- to 1.5-fold of GCH1 enzymes compared to untreated animals.

“These results provide proof-of-principle for continuous vector-mediated L-DOPA [dopamine] synthesis as a novel therapeutic strategy for Parkinson’s disease,” the researchers wrote.

“This gene therapy approach may thus offer the possibility to prolong and sustain the ‘good years’ many patients with Parkinson’s disease experience during the initial stages of L-DOPA therapy,” they added.

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Seelos Therapeutics Acquires Rights for Parkinson’s Gene Therapy Program

Gene therapy

Seelos Therapeutics has acquired the rights for a gene therapy program targeting the regulation of the SNCA gene, which provides instructions to make alpha-synuclein, a key player in the development of Parkinson’s disease.

The accumulation of abnormal (misfolded) alpha-synuclein protein can result in toxic aggregates that lead to the death of dopaminergic neurons. These toxic aggregates are the main component of Lewy bodies and Lewy neurites found in the brains of Parkinson’s patients.

“Aggregation of misfolded alpha-synuclein appears to be a key pathogenic mechanism leading to neuronal dysfunction and death. Inhibition of synuclein production, such as through SLS-004, is an attractive therapeutic target that may reduce aggregation and slow disease progression,” Robert A. Hauser, MD, director of Parkinson’s disease and movement disorders at the University of South Florida, said in a press release.

Methylation — the addition of specific chemical (methyl) groups that sit on top of a particular region within DNA — can regulate the activity of a gene mainly by “switching” it off. This strategy that regulates the activity of a gene without changing its DNA sequence is called an epigenetic approach.

SLS-004, developed by researchers at Duke University, uses a modified, harmless form of a virus, known as lentivirus, to deliver an enzyme called DNA methyltransferase 3A and promote the methylation of a particular region of the SCNA gene. This system is based on CRISPR-dCas9 gene editing technology and intends to fine-tune SNCA expression, thus lowering alpha-synuclein production.

“The down regulation of SNCA overexpression, through [a] one-shot epigenetic editing tool such as SLS-004, is a promising therapeutic approach, as it has shown reversal of the disease-related phenotypes preclinically,” said Tim Whitaker, head of R&D at Seelos Therapeutics.

In preclinical studies, delivery of SLS-004 to dopamine-producing neurons — those that are gradually lost in Parkinson’s — derived from stem cells from a Parkinson’s patient altered the expression of the SCNA gene and decreased levels of alpha-synuclein. Furthermore, the therapy protected against disease-related changes, including the production of harmful reactive oxygen species (ROS) and low cell viability.

“Under Seelos, we plan to move forward with this innovative CRISPR-dCas9-based development onto in vivo studies in [Parkinson’s disease] animal models,” said professor Ornit Chiba-Falek, a researcher at Duke University and co-inventor of SLS-004.

Boris Kantor, Ph.D., also a co-inventor of SLS-004, and colleagues are planning to develop “more efficient Cas9 variants, to further improve the accuracy and efficiency of the developed technology.”

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Man-made DNA Molecules May Help Prevent Parkinson’s, Study Finds

man made DNA molecules

Osaka University scientists have built short fragments of DNA that can stop the production of abnormal alpha-synuclein protein in the brain — which may advance the development of new therapies for the control and prevention of Parkinson’s disease.

The study, “Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease,” was published in Scientific Reports.

“Although there are drugs that treat the symptoms associated with PD [Parkinson’s disease], there is no fundamental treatment to control the onset and progression of the disease,” Takuya Uehara, PhD, the study’s lead author, said in a press release.

It is believed that gene therapy could someday be used to treat or halt Parkinson’s. Potential therapeutic targets include genes associated with the disorder, such as the SNCA gene — the gene that codes for the alpha-synuclein protein. Mutations in SNCA lead to the production and accumulation of an abnormal, and harmful, form of the alpha-synuclein protein within brain cells of people with Parkinson’s. As the disease progresses, neuronal toxic protein buildup increases, eventually leading to cellular death. That, in turn, leads to the onset of disease-related motor and non-motor symptoms.

“The antisense oligonucleotide (ASO) is a potential gene therapy for targeting the SNCA gene. ASO-based therapies have already been approved for neuromuscular diseases including spinal muscular atrophy (SMA) [Spinraza] and Duchenne muscular dystrophy [Exondys 51],” the researchers said.

Japanese researchers now looked for ways to prevent the production of toxic alpha-synuclein, hoping to eliminate Parkinson’s molecular trigger. To do so, they designed 50 small fragments of DNA that mirrored parts of  the coding sequence of the SNCA gene messenger RNA (mRNA).

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein.

The man-made DNA fragments, also known as amido-bridged nucleic acid-modified antisense oligonucleotides (AmNA-ASO), were stabilized with resilient cyclic amide structures (hence the term “amido-bridged”). Amide are compounds that confer structural rigidity.

In total, these 50 molecules covered around 80.7% of SNCA’s mRNA. In doing so, engineered molecules were able to bind to their matching natural mRNA sequence, disabling it from being translated into a protein.

Using human embryonic kidney cells that naturally produce alpha-synuclein, scientists observed that several of these engineered molecules reduced SNCA mRNA levels. One of the constructs, specifically number 19, significantly decreased SNCA mRNA levels to 24.5% of the normal alpha-synuclein levels, “suggesting that AmNA-ASO [number] 19 is highly potent for targeting SNCA mRNA in human cultured cells,” the researchers said.

Importantly, this particular ASO was efficiently delivered into the brains of mice using an intracerebroventricular (a fluid-filled interconnected brain cavity) injection, without the aid of additional chemical carriers. The ASO was then mainly taken up by neurons and neuronal support cells.

Further testing, using a Parkinson’s mouse model that had disease-characteristic motor impairment, revealed AmNA-ASO number 19 successfully reduced alpha-synuclein protein levels, and significantly eased symptom severity 27 days after administration.

The researchers concluded that reducing alpha-synuclein mRNA and corresponding protein levels via gene therapy seems to enhance Parkinson’s-related motor manifestations in mice. This highlighted AmNA-ASO’s potential as a novel therapy for this neurodegenerative disorder.

The ASO Spinraza (nusinersen) was approved by the U.S. Food and Drug Administration (FDA) in December 2016 for treating spinal muscular atrophy. The FDA granted accelerated approval to Exondys 51 (eteplirsen) in September 2016, making it the first drug approved to treat Duchenne muscular dystrophy.

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Potential One-time Gene Therapy for Parkinson’s Linked to GBA Mutations to Enter Clinical Trial

Parkinson's gene therapy trial

A potential gene therapy for Parkinson’s disease associated with mutations in the GBA1 gene, PR001, will move into clinical testing in patients after the U.S. Food and Drug Administration (FDA) accepted an application for the therapy, Prevail Therapeutics announced.

FDA acceptance of the company’s Investigational New Drug (IND) application allows Prevail to initiate a Phase 1/2 clinical trial assessing PR001’s safety and tolerability in Parkinson’s patients with disease-causing GBA1 mutations. Prevail expects to open the trial and begin dosing this year.

People with mutations in the GBA1 gene have a higher risk — possibly as high as five-fold — of developing Parkinson’s disease. Even though the exact relationship between both conditions is not clear, it is estimated that 7%–10% of all Parkinson’s cases are related to GBA1 mutations.

The GBA1 gene holds the instructions to produce the enzyme beta-glucocerebrosidase (GCase) that is active in lysosomesspecial compartments within cells that digest and recycle different types of molecules. If beta-glucocerebrosidase does not work as intended, toxic substances accumulate inside cells, particularly as people age, leading to excessive inflammation and —probably — the neurodegeneration seen in Parkinson’s disease.

PR001 is intended to be a disease-modifying and single-dose gene therapy for patients with mutations in this gene. It uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver a fully working copy of the GBA1 gene to nerve cells. This should allow for long-lasting expression of functional beta-glucocerebrosidase, easing disease symptoms caused by the mutated gene.

AAV-9 has been widely used in various gene therapies both approved and in clinical testing, including Zolgensma, a recently approved gene therapy to treat spinal muscular atrophy. The viral construct appears to be safe and can effectively cross the blood-brain barrier, a semipermeable membrane that separates blood from cerebrospinal fluid and protects the brain from viruses and other “invaders” entering via the bloodstream.  

“We are pleased that the FDA has accepted the IND for our first program, which we believe has the potential to transform the lives of patients with Parkinson’s disease with a GBA1 mutation,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

“At Prevail, our goal is to halt the progression of serious neurodegenerative diseases by applying precision medicine to the development of gene therapies. Our active IND brings us a step closer to achieving that goal, and we look forward to entering this new phase as a clinical-stage company,” he added.

Prevail, based in New York City, was founded in 2017 through a collaboration between Abeliovich,  OrbiMed and The Silverstein Foundation for Parkinson’s with GBA.

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