Six month results with low dose Prosavin gene therapy in Parkinson's Disease

Oxford, UK - 19 November 2008: Oxford BioMedica announced additional results from the low-dose cohort of patients in the Phase I/II trial of its novel gene therapy, ProSavin, for the treatment of Parkinson's disease. The three patients in this cohort showed improved motor function, as measured by the Unified Parkinson's Disease Rating Score (UPDRS) in the 'off' state, of an average of 30% at six months.
The safety profile of ProSavin has been maintained at six months with no evidence of adverse events or immunologic reactions to the treatment. In addition, all patients showed improvement in Quality of Life, as measured by the industry-standard PDQ-39 questionnaire, at six months.
The three patients that received the low dose of ProSavin demonstrated improvements in their UPDRS motor 'off' scores in the range of 10-50% after six months. This score measures the degree of mobility in the absence of standard of care dopaminergic therapies. One patient showed an improvement of up to 50% at six months, which was an increase from the three-month assessment, and another patient maintained an improvement of 30%. One patient showed an improvement of 10% at the six-month assessment compared to 23% at three months, although this patient's score may have been affected by adjustments to his L-DOPA 'equivalent' therapy.
The clinical evaluation of the high dose of ProSavin is progressing. There have been no safety issues to date and the preliminary data from the first patient treated at the high dose are promising.

Ceregene Announces Clinical Data from Phase 2 Clinical Trial of CERE-120 for Parkinson's Disease

San Diego, CA - November 26, 2008 – Ceregene, Inc., a biopharmaceutical company, today reported clinical data from a double-blind, controlled Phase 2 trial of CERE-120 in 58 patients with advanced Parkinson’s disease. The trial did not demonstrate an appreciable difference between patients treated with CERE-120 versus those in the control group. Both groups showed an approximate 7 point improvement in the protocol-defined primary endpoint (Unified Parkinson’s Disease Rating Scale- motor off score at 12 months), relative to a mean at baseline of approximately 39 points. Both groups had a substantial number of patients who demonstrated a meaningful clinical improvement from baseline. CERE-120 appeared to be safe and well tolerated.
“The medical research community has for several decades attempted to use the unique healing properties of neurotrophic factors to treat serious neurodegenerative diseases, and Ceregene’s use of gene therapy as an essential enabling technology to translate this idea into an effective human therapeutic has consistently generated strong empirical support,” stated Raymond T. Bartus, Ph.D., Ceregene’s executive vice president and chief scientific officer. “Thus, we are stunned by the results of this trial and will continue to analyze the data in order to gain greater insight into the factors that may have contributed to this negative outcome, not only to build upon this insight for our Parkinson’s program, but also to help assure continued successful development of our product candidates for other diseases.”

About Phase 2 Trial of CERE-120

Ceregene’s Phase 2 trial was a double-blind, controlled clinical trial that completed enrollment of 58 patients with advanced Parkinson’s disease in November 2007. This study was launched after successful execution of an extensive nonclinical program and preliminary evidence of safety and efficacy in advanced Parkinson’s patients via an open-label Phase 1 trial in 12 patients. Patients in the Phase 2 trial were enrolled across nine leading academic medical centers in the United States, with two thirds of patients receiving CERE-120 and one third enrolled into a control group. Patients received a single administration of CERE-120 via stereotactic neurosurgery to deliver the drug into the putamen region of the brain and were followed for 12 months for safety and efficacy.

About CERE-120

CERE-120 is composed of an adeno-associated virus (AAV) vector carrying the gene for neurturin (NTN), a naturally occurring protein known to repair damaged and dying dopamine-secreting neurons, keeping them alive and restoring normal function. NTN is a member of the same protein family as glial cell-derived neurotrophic factor (GDNF). The two molecules have similar pharmacological properties, and both have been shown to benefit the midbrain dopamine neurons that degenerate in Parkinson’s disease and are responsible for the major motor impairments. CERE-120 is delivered by stereotactic injection to the affected area of the brain, providing stable, long-lasting expression of NTN in a highly targeted fashion. Genzyme Corporation (Nasdaq: GENZ) has licensed the ex-North American rights for the development and commercialization of CERE-120 from Ceregene, an agreement that was announced in June 2007. Ceregene gratefully acknowledges the financial support received from the Michael J. Fox Foundation for Parkinson’s Research to help defray some of the costs of the CERE-120 Phase 1 and Phase 2 clinical trials.

Source: Ceregene (www.ceregene.com)

Mayo reports on early preclinical results with interfering RNA for Parkinson's

A group at the Mayo clinic have reported preclinical results of a new approach to treating Parkinson's disease.
Previous studies found that variations in the alpha-synuclein gene result in increased protein production and are sufficient to cause Parkinson’s disease in some families. The gene produces a protein that accumulates at the site and is linked with progress of the disease.
The Mayo team designed small RNA molecules which would interfere with process by which the alpha-synuclein protein is produced. Infusion of the small interfering RNA into the brains of mice effectively reduced alpha-synuclein production for up to three weeks with no ill-effects on the mice.
Work by other teams seeking to use gene therapy techniques to reprogram brain cells to continuously produce sufficient interfering RNAs to suppress target gene activity may offer a route to potential clinical treatment.
The publication is available here.

Reference: Lewis J, Melrose H, Bumcrot D, Hope A, Zehr C, Lincoln S, Braithwaite A, He Z, Ogholikhan S, Hinkle K, Kent C, Toudjarska I, Charisse K, Braich R, Pandey RK, Heckman M, Maraganore DM, Crook J, Farrer MJ. In vivo silencing of alpha-synuclein using naked siRNA. Mol Neurodegener. 2008 Nov 1;3(1):19.

Ideal Time For Stem Cell Collection Defined For Parkinson's Disease Therapy

ScienceDaily reports that a team from the Farber Institute for Neurosciences of Thomas Jefferson University have identified a stage during dopamine neuron differentiation that may be an ideal time to collect human embryonic stem cells for transplantation to treat Parkinson's disease. Read the article here.

New Research Helps Explain Genetics Of Parkinson's Disease

ScienceDaily (Nov. 25, 2008) reports a new study by researchers suggesting that Parkin, the product of the Parkinson's disease-related gene Park2, prompts neuronal survival by clearing the cell of its damaged mitochondria. Find the report here.

Reference: Parkin is recruited selectively to impaired mitochondria and promotes their autophagy D. Narendra, A. Tanaka, D.-F. Suen, and R.J. Youle. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol., 2008; DOI: 10.1083/jcb.200809125

Subthalamic nucleus DBS modulates thalamic neuronal activity

This month's Journal of Neuroscience carries a paper by a team from the Cleveland Clinic, Ohio, USA studying the mechanism by which subthalamic DBS elicits its beneficial clinical effect. The authors state the findings "are consistent with the hypothesis that STN DBS increases output from the nucleus and produces a change in the pattern and periodicity of neuronal activity in the basal ganglia thalamic network, and that these changes include cerebellar pathways likely via activation of adjacent cerebello-thalamic fiber bundles". To read the abstract click here.

Reference: J Neurosci. 2008 Nov 12;28(46):11916-24.

Brazilian tree may promise neuroprotective treatment.

Writing in the Nov 13, 2008 edition of Neurochemical Research a team from Brazil confirm that extracts from stem bark of a Brazilian medicinal plant, Myracrodruon urundeuva, is neuroprotective against 6-hydroxydopamine (6-OHDA)-induced neuronal cell death, in rat mesencephalic cells. (6-OHDA or 6-Hydroxydopamine, is a neurotoxin used by neurobiologists to selectively kill dopaminergic and noradrenergic neurons. The main use for 6-OHDA in scientific research is to induce Parkinsonism in laboratory animals such as mice, rats and monkeys, in order to develop and test new medicines for treating Parkinson's disease in humans).
This confirms previous observations reported in 2006 suggesting the neuroprotective effect of the bark extracts involves mitochondrial protection and antioxidant activity.

References:

Nobre-Júnior HV, Oliveira RA, Maia FD, Nogueira MA, de Moraes MO, Bandeira MA, Andrade GM, Viana GS. Neuroprotective Effects of Chalcones from Myracrodruon urundeuva on 6-Hydroxydopamine-Induced Cytotoxicity in Rat Mesencephalic Cells.
Neurochem Res. 2008 Nov 13. [Epub ahead of print]

Nobre-Junior, Flavio D. Maia, Ricardo A. de Oliveira, Mary Anne Medeiros Bandeira, Claudia do O Pessoa, Manoel O. Moraes, Geanne M. A. Cunha, Glauce S. B. Viana. Neuroprotective Actions of Tannins from Myracrodruon urundeuva on 6-Hydroxydopamine-Induced Neuronal Cell Death Journal of Herbs, Spices & Medicinal Plants Volume: 13 Issue: 2

Patients treated with unilateral DBS eventually require bilateral treatment.

Writing in this months edition of the journal Movement Disorders, Kim et al from Korea report on two year follow up of eight patients with highly asymmetric Parkinson's disease who were treated with unilateral subthalamic deep brain stimulation (DBS). The intervention produced the expected improvement on the treated side of the body. However, the symptoms on the untreated side progressively worsened and the reversed asymmetry became difficult to manage, which led to compromised medication and stimulator adjustment. At 24 months, all the patients were considering the second-side surgery. The authors interpret their observations as indicating that bilateral STN DBS should be considered in patients even in even if their Parkinson's symptoms are markedly asymmetrical at the time of surgery.

Reference: Movement Disorders 2008 Nov 12 (Electronic publication ahead of print)

Transplanted nerve cells develop Parkinson's changes: A second case report.

Kordower, Chu, Hauser and Olanow from the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA, have reported pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term. The report appears in the November edition of Movements Disorders.

Reference: Movement Disorders 2008 Nov 12. [Epub ahead of print]

Patient screening for phase II gene theray "well underway"

Neurologix Inc is a New Jersey based biotech company developing a gene therapy for Parkinson's disease. Using an AAV viral vector to introduce the gene coding for production of GAD enzyme the aim of the treatment is to increase levels of a gamma aminobutyric acid ("GABA") in the subthalamic region and inhibiting the overactivity of this part of the brain which is central to Parkinson's disease symptoms. Results of the first study in humans were published in The Lancet in 2007 and suggested acceptable safety and statistically significant suggestions of of activity (though this first study lacked placebo control).

"Patient screening for our Phase 2 clinical trial of our investigational gene therapy procedure for the treatment of Parkinson's disease is well underway at multiple clinical trial sites," said Mr. Mordock, President and CEO of Neurologix.

"Also, during the third quarter we announced the licensing of exclusive rights from Aegera Therapeutics to a key gene with potential use as a therapeutic, neuroprotective factor in the treatment of Huntington's disease," explained Mr. Mordock. "Our preclinical studies with a mutated form of this gene, known as XIAP (x-linked inhibitor of apoptosis protein), have shown that when delivered via our Adeno-Associated Virus (AAV) vector into the brains of mice harboring the same mutation that causes Huntington's disease in humans, the gene can not only slow the disease, but can actually normalize motor deficits associated with Huntington's. We look forward to moving this indication towards human clinical trials during 2009."

Chronic activation of the D2 dopamine autoreceptor inhibits synapse development

Chronic activation of dopamine receptors is critical for the pharmacological treatment of Parkinson's disease. However, the long-term impact of such treatment on dopamine neurons is unclear. Fasano et. al. publishing in this months European Journal of Neuroscience suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. The study was conducted in mice. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin (mTOR) pathway of mRNA translation was blocked a finding which may offer pharmacological strategies for mitigating some of the side-effects of long term dopamine stimulation required to treat Parkinson's disease.

Reference: Eur J Neurosci 2008 Oct;28(8):1480-90.

DJ-1 protects against dopamine toxicity.

Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The full function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, and led to the to the suggestion that DJ-1 is protective under these conditions. In 2005 a group from Tufts University School of Medicine, Boston, MA, USA published work to show that the Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis (cell death). (Ref 1). Xu et. al. showed the "major interacting-proteins with DJ-1 in dopaminergic neuronal cells are the nuclear proteins p54nrb and pyrimidine tract-binding protein-associated splicing factor (PSF), two multifunctional regulators of transcription and RNA metabolism. PD-associated DJ-1 mutants exhibit decreased nuclear distribution and increased mitochondrial localization, resulting in diminished co-localization with co-activator p54nrb and repressor PSF. Unlike pathogenic DJ-1 mutants, wild-type" (i.e. non-mutated) "DJ-1 acts to inhibit the transcriptional silencing activity of the PSF. In addition, the transcriptional silencer PSF induces neuronal apoptosis, which can be reversed by wild-type DJ-1 but to a lesser extent by PD-associated DJ-1 mutants. DJ-1-specific small interfering RNA sensitizes cells to PSF-induced apoptosis. Both DJ-1 and p54nrb block oxidative stress and mutant alpha-synuclein-induced cell death." Thus, wild-type DJ-1 is a neuroprotective in dopaminergic neurons vulnerable to apoptosis.
This month's Journal of Neural Transmission (Ref 2) includes a report by Lev et. al. from Israel, suggesting that normal DJ-1 protein protects against dopamine toxicity. DJ-1 mutations associated with early onset Parkinson's disease however may not offer this protection. The authors show that " DJ-1 protects against dopamine toxicity. Dopamine-exposure led to upregulation of DJ-1. Overexpression of DJ-1 increased cell resistance to dopamine toxicity and reduced intracellular reactive oxygen species. Contrary effects were achieved when DJ-1 levels were artificially reduced reduced (by siRNA.) Similarly, in vivo striatal administration of 6-hydroxydopamine led to upregulation of DJ-1. Upregulation of DJ-1 was mediated by the MAP kinases pathway through activation of ERK 1, 2 in vitro and in vivo. Hence, oxidative stress, generated by free cytoplasmic dopamine, leads to upregulation of DJ-1 through the MAP kinases pathway."

References:

1) Hum Mol Gent. 2005 May 1;14(9):1231-41. Epub 2005 Mar 24.

2) J Neural Transm. 2008 Oct 31. [Epub ahead of print]

Galantamine for dementia in patients with Parkinson's disease

Litvinenko and colleagues from the Department of Nervous Diseases, Military Medical Academy, St. Petersburg, Russia have published results of an, open (i.e. not blinded), controlled study to assess the safety and efficacy of galantamine (Remidyl) in 41 patients with Parkinson's disease with dementia. Twenty-one patients received galantamine at a maximum dose of 16 mg/day. The remaining 20 patients did not receive the drug but were observed as a control group.
Cognitive, neuropsychiatric, and motor symptoms were assessed clinically before the trial and at 4, 12, and 24 weeks, using the Mini Mental State Examination (MMSE), the cognitive Alzheimer's Disease Assessment Scale (ADAS-cog), the clock drawing test, the Frontal Assessment Battery (FAB), and the Neuropsychiatric Inventory (NPI) with assessment of distress in relatives. Patients treated with galantamine had better scores on the MMSE (p < 0.05),ADAS-cog (p < 0.05), the clock drawing test (p < 0.05), and the FAB (p < 0.01) at the end of the study period as compared with the control group. Changes in total point scores on the NPI-12 at the ends of weeks 12 and 24, as compared with the beginning of the trial, were in favor of the group treated with galantamine, with significant changes in the hallucinations (p = 0.0002), anxiety (p = 0.04), sleep disturbance (p = 0.04), and apathy (p = 0.006) sections. Galantamine treatment was accompanied by decreases in the level of distress in patients' relatives (p = 0.007) and improvements in daily activity (p = 0.003). Improvements in gait and decreases in freezing and falls were seen in the galantamine treatment group. However, two patients of this group showed minor increases in tremor. Side effects (drooling, postural hypotension, nausea, dysuria) occurred in seven patients (30%).

Reference: Neurosci Behav Physiol. 2008 Oct 31. (electronic publication prior to journal publication

For more information on galantamine click here.

Gout appears to protect against Parkinson's Disease

Several studies have suggested that higher serum uric acid levels
lead to a lower risk of Parkinson's disease (PD) because uric acid exerts
antioxidant effects on neurons.
A team led by Dr M De Vera from the Arthritis Research Centre of Canada and University of British Columbia, Vancouver, Canada have published results of a further study to explore this relationship.
Results of their study show evidence for a protective effect of gout on the risk of Parkinson's disease and support the purported protective role of uric acid.

Reference: Arthritis Rheum. 2008 Oct 30;59(11):1549-1554.