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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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Gene Therapy Candidate AXO-Lenti-PD Continues to Benefit Parkinson’s Patients in SUNRISE-PD Trial

SUNRISE-PD AXO-Lenti-PD

A single dose of Axovant’s gene therapy candidate AXO-Lenti-PD continues to improve motor function and has been well-tolerated after six months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

“We continue to be encouraged by the consistency of the data and improvements in quality of life seen at six months in the two low-dose cohort patients, as we enroll additional patients in the second cohort of the SUNRISE-PD study,” Gavin Corcoran, chief research and development officer at Axovant, said in a press release.

Patient enrollment is ongoing for up to 30 participants, ages 48–70, who have been diagnosed with idiopathic (of unknown cause) Parkinson’s for at least five years. More information on contacts and trial locations (in Europe) is available here.

AXO-Lenti-PD is a gene therapy that uses a harmless virus-based system to deliver three genes that generate three enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase for the production of dopamine, the brain-signaling molecule that is present in low levels in Parkinson’s patients.

The therapy is administrated surgically directly into the brain to restore dopamine levels and provide long-lasting benefits with a single administration.

“Our patient-focused goal of improving motor function, reducing dyskinesia, lowering the requirement for oral levodopa, and improving quality of life is made possible by the continuous dopamine replacement strategy of AXO-Lenti-PD gene therapy,” Corcoran said.

The SUNRISE-PD (NCT03720418) study consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of approximately three escalating doses of the gene therapy. In part B of SUNRISE-PD, patients are then randomized to receive either the selected dose from part A or an imitation surgical procedure (control group). The goal is to test the safety, tolerability, and effectiveness of the potential treatment.

The first two patients enrolled received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD. In March, Axovant revealed results of three months of follow-up.

Now, at six months of follow-up, the patients experienced an average improvement of 17 points in motor function, as measured using the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) Part III, which represents an average 29% change from the beginning of the study.

The patients also showed an average improvement of about 20 points from baseline on the UPDRS Part II (activities of daily living) off score, and an average improvement of 3 points from baseline on the UPDRS Part IV (dealing with complications of therapy) off score. “Off time” is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

Treatment with AXO-Lenti-PD also was associated with an average reduction of 21% in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at six months.

Data also revealed a mean 18% improvement in dyskinesia — involuntary, jerky movements — at six months, determined with the Rush Dyskinesia Rating Scale “on time” score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients experienced an improvement in on time without dyskinesia of 2.7 hours, a reduction in on time with non-troublesome dyskinesias of 2.4 hours, a reduction of on time with troublesome dyskinesia of 1.5 hours, and an increase in off time of 0.9 hours.

In addition, the patients reported significant improvements in their quality of life, achieving a reduction of 32 points (65% improvement) from baseline in the Parkinson’s Disease Questionnaire-39 Summary Index score.

“These data at six months highlight the potential for a clinically meaningful improvement over the currently available standard of care for those patients with moderate to advanced Parkinson’s disease,” Corcoran said.

Three-month data from SUNDRISE-PD patients treated with the second dose of AXO-Lenti-PD is expected to be announced during the fourth quarter of this year.

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#AANAM — Investigational VY-AADC01 Gene Therapy Provides Benefits for Parkinson’s Patients, Phase 1 Data Show

VY-AADC01 Phase 1 trial

A single-dose infusion of VY-AADC01, an investigational gene therapy, improves motor function and reduces the need for antiparkinsonian medications in advanced Parkinson’s disease patients, results from the Phase 1 PD-1102 clinical trial show.

Trial findings were presented in a scientific poster, titled “PD-1102: A Phase 1 study of VY-AADC01 Administered Using a Posterior Approach in Patients with Parkinson’s Disease and Motor Fluctuations,” during the 2019 American Academy of Neurology (AAN) annual meeting, taking place through May 10 in Philadelphia.

VY-AADC01, a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics, delivers the AADC gene directly into a specific brain area called the putamen, a large structure filled with dopamine receptors. This gene carries the information for the production of the L-amino acid decarboxylase (AADC) enzyme that mediates the conversion of levodopa into dopamine.

Death of dopaminergic neurons and a reduction in AADC enzyme levels are two key underlying features of Parkinson’s. The strategy of delivering the AADC enzyme into brain cells is aimed at restoring the conversion of levodopa and increasing dopamine production.

PD-1102 (NCT03065192) is an ongoing open-label Phase 1 trial evaluating the safety and efficacy of a single dose of VY-AADC01 — 9.4 × 1012 vg — injected directly into the striatum using a surgical approach in which the gene therapy is delivered through the back of the patient’s head (posterior surgical approach).

Another ongoing Phase 1b trial, called PD-1101 (NCT01973543), is evaluating the safety and efficacy of ascending doses of VY-AADC01 — 7.5 × 1011 vector genomes (vg), 1.5 and 4.7 × 1012 vg — whereby the gene therapy is injected directly into the striatum of 15 Parkinson’s patients via a surgical procedure through the top of the head (frontal surgical approach). The surgical intervention is aided by real-time magnetic resonance imaging (MRI) to monitor the gene therapy’s delivery.

Interim results of this trial reported dose-dependent improvements in motor function, patients’ quality of life, and reduction of antiparkinsonian medications.

The new neurosurgical strategy employed in the PD-1102 trial is thought to decrease the infusion time while enhancing the gene therapy’s coverage of its targeted brain area.

PD-1102’s main objectives include safety and measures of efficacy, such as coverage of the putamen brain area, AADC activity, changes in motor function and in dyskinesia (the abnormal involuntary movements that characterize advanced Parkinson’s), use of antiparkinsonian medications, and patients’ reported on and off times.

Off periods in Parkinson’s are characterized by the reappearance or worsening of symptoms — such as tremors and dyskinesia — due to a gradual decline in levodopa’s therapeutic effectiveness. These symptoms become more frequent and severe as the disease progresses.

The trial enrolled eight patients, at a mean age of 56.8 years, with advanced Parkinson’s (mean disease duration of 9.2 years) and with similar characteristics to those enrolled in the PD-1101 study. 

At the start of the trial, patients’ mean off time was 6.8 hours, while the mean on time (the period when levopoda is working) was 9.1 hours.

Administration of a single dose of VY-AADC was able to cover 54% of the putamen brain area. Moreover, infusion of the gene therapy took 3.1 hours, two hours less than the time of infusion in the PD-1101 trial (5.2 hours).

Treatment with VY-AADC increased AADC enzyme activity in the putamen area by 85%, which reflects the ability of neurons to convert levodopa to dopamine.

Compared with the beginning of the study, the gene therapy improved patients’ motor function at 12 months and improved patients’ good on time (on time without troublesome dyskinesia) by 1.7 hours and reduced off time by 2.2 hours after 12 months.

The treatment also lowered patients’ use of antiparkinsonian medications by 28% six and 12 months after infusion.

Exploratory analyses in four patients with low or no dyskinesia or absence of impulse control disorder at the start of the trial showed that a single infusion of VY-AADC in this group led to greater improvements, with good on time increased by 3.2 hours and off time reduced by 3.2 hours after 12 months.

Infusions of VY-AADC were well-tolerated with no serious adverse events.

VY-AADC also improved patients’ quality of life, as measured by the 39-item Parkinson’s Disease Questionnaire, a self-administered questionnaire that addresses aspects of functioning and well-being. Patients’ mean scores decreased — or improved — by 7.6 points after 12 months.

“The results from this Phase I trial in patients with Parkinson’s disease provide further evidence that VY-AADC administration can allow neurons in the brain to convert levodopa to dopamine and improve motor function,” Eiry W. Roberts, MD, chief medical officer of Neurocrine, said in a press release.

“[These results] confirm previous data from a separate, ongoing Phase I study demonstrating that increased coverage of the putamen with VY-AADC leads to an increase in AADC enzyme activity and improvements in motor function and quality of life in patients with Parkinson’s disease — with less need for oral levodopa medication,” he added.

Based on the positive results from both the PD-1101 and PD-1102 trials, researchers have launched the RESTORE-1 Phase 2 trial (NCT03562494). The trial, currently recruiting participants, will randomize patients with advanced Parkinson’s disease who have failed to respond properly to oral therapy to either optimized medical management plus VY-AADC01 or continued optimized medical management — including levodopa — plus placebo-surgery.

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Voyager’s Gene Therapy Shows Positive Interim Results in Phase 1b Trial

Gene therapy

An investigational gene therapy being developed for the treatment of Parkinson’s disease was well-  tolerated and eased patients’ motor fluctuations in a dose-dependent manner after a one-time administration, according to interim results.

The study, “Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease,” was published in Annals of Neurology.

VY-AADC01 is a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics. It uses a viral vector (AAV) to deliver the AADC gene — which codes for an enzyme called L-amino acid decarboxylase (AADC) and mediates the conversion of levodopa into dopamine — directly into a specific brain area called the putamen, a large structure filled with dopamine receptors.

Death of dopaminergic neurons and a reduction in AADC enzyme levels are two fundamental mechanisms underlying Parkinson’s disease. By delivering the AADC enzyme into brain cells, researchers aim to restore the conversion of levodopa and increase dopamine production.

The open-label, Phase 1b study (NCT01973543) enrolled 15 people (13 men and two women, mean age 57.7 years) with moderately advanced Parkinson’s disease and fluctuating responses to levodopa. Subjects were divided into three groups and treated with ascending doses of VY-AADC01 (7.5 × 1011vector genomes (vg); 1.5 × 1012vg; 4.7 × 1012vg).

The therapy was administered in a single-dose infusion using magnetic resonance imaging (MRI) to guide its delivery. Group 1 (lower dose) was followed for up to three years, group 2 through two years, and group 3 (higher dose) for up to 1.5 years. During the study, patients kept taking their antiparkinsonian medications, including levodopa.

The trial’s primary goals were the safety, tolerability, and distribution of ascending doses of VY-AADC01. Secondary objectives included AADC activity changes in response to levodopa, clinical outcomes over a year, and the durability of those changes after 12 months.

Results showed that large-volume administrations of VY-AADC01 were well-tolerated. At six months post-treatment, the MRI-guided delivery approach increased the coverage area reached by the gene therapy: coverage of 21% in group 1, 34% in group 2 and 42% in group 3. This was found to be closely correlated with increases in AADC activity: 13%, 56%, and 79%, respectively. The increase in putaminal coverage was also related to reductions in the patients’ medication regimen: 15% less in group 1, 33% less in group 2 and 42% less in group 3.

A year after treatment, investigators observed VY‐AADC01 dose-dependent improvements in motor fluctuations, motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS part III) and patients’ quality of life, despite reductions in antiparkinsonian medications.

Patients reported increases in their “on” periods (when medication does not wear off and motor symptoms are controlled) without experiencing troublesome abnormal involuntary movements (dyskinesia).

“The interim results from this Phase 1b trial demonstrated that administration of [VY-AADC01] to the putamen using a novel technique, which included intraoperative monitoring with magnetic resonance imaging guidance, facilitated targeted delivery of the investigational gene therapy,” Chad Christine, MD, professor of neurology, University of California, San Francisco and investigator in this trial, said in a news release.

“Additionally, administration of [VY-AADC01] resulted in dose-dependent increases in AADC enzyme expression and improvements in clinical measures and has been well-tolerated to date,” he said.

Based on these open-label results, researchers have initiated the RESTORE-1 Phase 2 trial (NCT03562494) to evaluate the safety and efficacy of VY-AADC01 and understand “its efficacy relative to optimal medical management alone,” they said.

The trial, which is recruiting, will randomize patients with advanced Parkinson’s disease who have not responded adequately to oral therapy to either optimized medical management plus VY-AADC01 or continued optimized medical management — including levodopa — plus placebo-surgery. Researchers plan to enroll 42 participants.

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AXO-Lenti-PD Gene Therapy Shows Benefits in 2 Advanced Parkinson’s Patients in Phase 1/2 Trial

AXO-Lenti-PD

One-time treatment with the gene therapy candidate AXO-Lenti-PD led to improved motor function and was well-tolerated after three months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

These findings are from the open-label, dose-escalation portion of the SUNRISE-PD study (NCT03720418), in which the patients received the lowest dose (4.2×106 TU) of Axovant’s AXO-Lenti-PD. The goal is to test the safety, tolerability, and efficacy of the potential treatment.

“These findings are highly encouraging, and we look forward to advancing to higher dose cohorts where we will explore the full clinical potential of AXO-Lenti-PD in patients with Parkinson’s,” Gavin Corcoran, Axovant’s executive vice president of research and development, said in a press release.

Patient enrollment is ongoing in the U.K. (yet to open in France) for a total of about 30 participants ages 48–70 who have been diagnosed with idiopathic Parkinson’s for at least five years. More information on contacts and trial locations is available here.

AXO-Lenti-PD uses a harmless virus-based system to deliver three genes that generate key enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase — for the production of dopamine, the neurotransmitter found at reduced levels in Parkinson’s patients. The gene therapy — delivered surgically directly into the brain — is aimed at restoring dopamine levels in the brain to provide long-lasting benefits with a single administration.

As measured with the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) part III off score — assessed after levodopa washout to not throw off the results — the two patients experienced a 25-point improvement in motor function, which represents an average 42% change from the beginning of the study. Off time is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

The benefits were observed across all subparts of the UPDRS scale, with an overall improvement of 54.5 points, or 55% from before treatment. In UPDRS part II, which refers to activities of daily living, average improvements were 22 points, and in part IV, dealing with complications of therapy, the patients showed a seven-point improvement.

Data further showed a mean 18% improvement in dyskinesia — involuntary, jerky movements — determined with the Rush Dyskinesia Rating Scale on score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients had an improvement in on time with dyskinesia and troublesome dyskinesia, with average decreases from before treatment of 3.5 hours (or 57%) and 1.3 hours (85%), respectively.

Treatment with AXO-Lenti-PD was also associated with an average reduction of 208 mg (19%) in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at three months. No serious adverse events were reported.

Results of a Phase 1/2 trial (NCT00627588) of ProSavin, the predecessor to AXO-Lenti-PD, had shown favorable safety and tolerability, as well as significant improvement in motor function, at four years of treatment in most patients.

Compared with ProSavin, preclinical data of AXO-Lenti-PD showed higher production of the crucial enzymes and a minimum fivefold greater potency in improving behavior and movement in an animal model of Parkinson’s disease.

“These early data support the safety of the lowest dose of AXO-Lenti-PD, similar to what was observed with the earlier generation construct, ProSavin, and also suggest substantially greater biological activity than the highest dose of ProSavin previously tested,” Corcoran said.

Roger Barker, one of the principal investigators in SUNRISE-PD, said the results suggest that AXO-Lenti-PD “has the potential to significantly improve motor function in patients with advancing Parkinson’s.”

He also said that given the mechanism of action of AXO-Lenti-PD and the experience with ProSavin, the scientists expected the main benefit to be in relieving the off state — “and the results so far are very encouraging in this regard.”

Axovant is now planning to proceed to the second dose group (1.4×107) after receiving positive feedback from the trial’s data monitoring committee. Dosing of the first patient in this second group is expected in the second quarter of this year.

“I am hopeful that this development program will translate into a significant new therapeutic option for patients with Parkinson’s,” said Baker, a professor of clinical neuroscience and honorary consultant in neurology at the University of Cambridge and Addenbrooke’s Hospital.

Axovant recently gave a presentation at the Cowen and Company 39th Annual Health Care Conference in Boston. A copy of the slides and link to a webcast can be found here.

In June 2018, Axovant obtained exclusive worldwide rights to AXO-Lenti-PD from Oxford BioMedica, which originally developed the gene therapy.

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Gene Therapy Preserves Nerve Fibers in Mouse Model of Severe Neurodegeneration

Gene therapy

An investigational gene therapy was able to preserve nerve axons — long projections that connect nerve cells and transport information — in a mouse model of severe axonal degeneration.

Because axon degeneration precedes the death of neurons in several neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the findings support this therapy’s potential as an effective treatment.

The study, “Gene therapy targeting SARM1 blocks pathological axon degeneration in mice,” was published in the Journal of Experimental Medicine.

Axons, or nerve fibers, are the long projections of a nerve cell, which conduct electrical impulses away from the cell body to other nerve cells, muscles, and glands. There is currently no treatment that effectively inhibits axon degeneration.

When an axon is injured, a protein called SARM1 becomes activated and triggers axons to self-destruct. In healthy nerve cells, this protein is switched off. Deleting the gene that codes for this protein, the SARM1 gene, has been shown to have a protective effect against axonal degeneration after injury in both a fruit fly model and a mouse model.

SARM1 acts as an enzyme that destroys metabolic factors needed for axons to work properly. It works by rapidly degrading a metabolite, called NAD+, causing a metabolic failure in neurons that trigger axonal degeneration. When this protein is mutated, it prevents rapid energy loss and subsequent destruction of axons.

SARM1’s multiple components must bind together for the protein to work properly. If one of these components is changed, the protein’s assemblage is faulty and unable to function. As such, scientists only have to alter or mutate a part of the protein to inhibit its function.

Researchers at St. Louis’ Washington University School of Medicine have developed a gene therapy to block the activity of SARM1.

The team introduced single mutations, affecting only one nucleotide — the building blocks of DNA — in the SARM1 gene, which resulted in the production of a faulty SARM1 protein. Similar to neurons without the SARM1 gene, when this gene therapy was inserted into nerve cells grown in the laboratory, no axonal degeneration was observed.

Accordingly, in injured neurons with a normal SARM1 protein, NAD+ levels were reduced. However, upon treatment with the gene therapy, they remained constant.

Researchers then treated neurons with vincristine, a chemotherapy agent, to simulate nerve cell damage. Two days later, the treatment resulted in axonal fragmentation. However, neurons that received the gene therapy remained intact and had normal metabolic activity — proof of how the therapy was able to inhibit SARM1 function.

To test the gene therapy in living organisms, the team used an inactive virus — adeno-associated virus (AAV) — as a vehicle to deliver the therapy into nerve cells of a mouse model of severe axonal degeneration. Researchers had induced a severe nerve injury in the sciatic nerve to trigger axonal degeneration.

Within five weeks, the viral vector containing the altered SARM1 gene was present in several of the affected nerves, including peripheral nerves and spinal cord nerve cells.

In animals treated with the gene therapy, their axons remained intact up to 10 days after nerve injury, and neurons preserved their normal conformation, architecture and myelin — a protective coating around nerve fibers — thickness.

In control (untreated) mice, there was almost a complete (99%) loss of axons at sites of nerve injury.

“With our viral gene therapy, we delivered a mutated form of SARM1 that is not only inactive itself but also blocks normal SARM1 proteins that have become activated in mice with nerve injuries,” senior author Jeffrey D. Milbrandt, MD, PhD, said in a university news release. “For a long time, viral gene therapy was a pipe dream, but there are now a number of ongoing clinical trials in other disorders that suggest we are on a promising track.”

“This has the potential to be transformative because it cuts across so many diseases,” said co-senior author Aaron DiAntonio, MD, PhD. “Rather than addressing a single disease, it is potentially a treatment for a disease process that is shared among many different neurodegenerative disorders.”

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