modified glial cell-derived neurotrophic factor (GNDF) / Medtronic, Eli Lilly, uniQure - LARVOL DELTA

Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling. (PubMed, Nat Commun) - "Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. Thus, BDNFmNTS neurons are required for the weight-reducing actions of both GDF15 and the GLP1RA, Exendin-4. Moreover, acute activation of BDNFmNTS neurons is sufficient to reduce food intake and drive fatty acid oxidation and might provide a route for longer-term weight loss."

Journal • BDNF • GDF15

uniQure announces start of Parkinson’s disease gene therapy Phase I trial by UCSF/NIH to test its GDNF gene in patients (UniQure Press Release) - "uniQure...announced the start of a human trial in Parkinson’s disease with glial cell line-derived neurotrophic factor (GDNF). The study is a Phase I open-label dose escalation safety study that will include 24 patients divided over 4 cohorts."

Enrollment change • New P1 trial • Parkinson's Disease

[TRANSPLANTATION OF NEURAL STEM CELLS INDUCED BY ALL-TRANS- RETINOIC ACID COMBINED WITH GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR AND CHONDROITINASE ABC FOR REPAIRING SPINAL CORD INJURY OF RATS]. (PubMed) - Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi - "The NSCs transplantation combined with GDNF and ChABC could significantly promote the functional recovery of spinal cord injury, suggesting that GDNF and ChABC have a synergistic effect in the treatment of spinal cord injury."

Journal • Biosimilar • Complement-mediated Rare Disorders • Inflammation

NODAL secreted by male germ cells regulates the proliferation and function of human Sertoli cells from obstructive azoospermia and nonobstructive azoospermia patients. (PubMed) - "There was not homogeneity of genes changes by NODAL treatment in Sertoli cells from OA and Sertoli cell-only syndrome (SCO) patients. Collectively, this study demonstrates that NODAL produced by human male germ cells regulates proliferation and numerous gene expression of Sertoli cells."

Journal • Biosimilar

Purine nucleosides in neuroregeneration and neuroprotection. (PubMed) - Neuropharmacology - "A most novel part of the review focus on the mechanisms of neuronal regeneration that are targeted by nucleosides, including a recently identified action of adenosine on axonal growth and microtubule dynamics. Discussion on the role of the purine nucleosides transversally with the most established neurotrophic factors, e.g. brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), is also focused considering the intimate relationship between some adenosine receptors, as is the case of the A2A receptors, and receptors for neurotrophins."

Journal • Review • Biosimilar

Peptide profiling of Internet-obtained Cerebrolysin using high performance liquid chromatography - electrospray ionization ion trap and ultra high performance liquid chromatography - ion mobility - quadrupole time of flight mass spectrometry. (PubMed) - "The main components in this sample originate from tubulin alpha- and beta-chain, actin, and myelin basic protein. No fragments of known neurotrophic factors like glial cell-derived neurotrophic factor (GDNF), neurotrophin nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) were found, suggesting that the activities reported in the literature are likely the result of new, hitherto unknown cryptic peptides with nootropic properties."

Journal • Biosimilar

An engineered biocompatible drug delivery system enhances nerve regeneration after delayed repair. (PubMed) - "The DDS increased neuron regeneration to levels double those observed with negative control groups. This biocompatible, non-toxic, fibrin gel-based DDS enhances outcomes following severe peripheral nerve injuries."

Journal • Biosimilar

Targeting exogenous GDNF gene to the bovine somatic cell beta-casein locus for the production of transgenic bovine animals. (PubMed) - Genet Mol Res - "Gene-targeted cells were used as nuclear donors; a total of 161 embryos were reconstructed, 23 of which developed to the blastocyst stage. These blastocysts were transferred to 8 recipient cows, but no offspring were obtained."

Journal • Biosimilar • Gene Therapies • Parkinson's Disease

Basic Research on Neurotrophic Factors and Its Application to Medical Uses. (PubMed) - "2-Decenoic acid derivatives and other similar molecules could protect or ameliorate in animal models of mood disorders such as depression and enhance recovery from spinal cord injury-induced motor paralysis. Compounds that can generate neurotrophin-like signals in neurons are expected to be developed as therapeutic drugs for certain neurological or psychiatric disorders."

Journal • Biosimilar • Depression

Optimized quantities of GDNF overexpressed by engineered astrocytes are critical for protection of neuroblastoma cells against 6-OHDA toxicity (J Mol Neurosci) - SK-N-MC cell survival rate rose from 51% in control group to 84% in the cells grown with astro-CM containing 453 pg secreted GDNF, an increase that was highly significant (p<0.0001); Larger volumes of the GDNF-enriched conditioned medium failed to improve cell survival and addition of volumes that contained 1,600 pg or more GDNF further reduced survival rate to below 70%.

Preclinical-other • Parkinson's Disease

Glial Cell Line-Derived Neurotrophic Factor Protects Against High Fat Diet-Induced Hepatic Steatosis by Suppressing Hepatic PPAR-γ Expression. (PubMed) - Am J Physiol Gastrointest Liver Physiol - "In vitro, GDNF suppressed triglyceride accumulation in HepG2 cells through enhanced p38 MAPK-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of NAFLD."

Journal • Biosimilar • Fibrosis • Immunology • Inflammation • Systemic Sclerosis

Effects of glial cell line-derived neurotrophic factor on microRNA expression in a 6-hydroxydopamine-injured dopaminergic cell line (J Neural Transm) - PMID: 23771700; "...various biological processes and pathways were regulated at the miRNA level following GDNF treatment...results provide evidence of the capacity of GDNF to influence miRNAs expression, suggesting a new mechanism of GDNF action."

Preclinical • Parkinson's Disease

Intranasal Administration of Glial-Derived Neurotrophic Factor (GDNF) Rapidly and Significantly Increases Whole Brain GDNF Level in Rats. (PubMed) - "Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD."

Journal • Biosimilar • Parkinson's Disease

A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses. (PubMed) - Mol Ther Methods Clin Dev - "Motor asymmetry resulting from unilateral GDNF treatment only appeared with a 2.5-fold higher vector and a 13-fold higher inducer doses. Our data suggest that using the herein-described inducible AAV vector, biological effects of GDNF can be obtained in response to sub-antimicrobial doxycycline doses."

Journal • Biosimilar

A mathematical model for the induction of the mammalian ureteric bud. (PubMed) - J Theor Biol - "Our model demonstrates that this proposed pattern formation mechanism is capable of naturally predicting the phenotypical outcomes of many genetic experiments from the literature. Furthermore, we conclude that whilst BMP inhibits GDNF away from the budding site and GREM1 permits GDNF to signal, GREM1 also stabilises the effect of BMP on GDNF signalling from fluctuations in BMP sensitivity but not signal strength."

Journal • Biosimilar

Chitosan scaffolds induce human dental pulp stem cells to neural differentiation: potential roles for spinal cord injury therapy. - Cell Tissue Res - "Thus, chitosan scaffolds were non-cytotoxic and provided a conducive and favorable microenvironment for the survival and neural differentiation of DPSCs. Transplantation of DPSCs might therefore be a suitable candidate for treating SCI and other neuronal degenerative diseases."

Journal • Biosimilar • Complement-mediated Rare Disorders

Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier. (PubMed) - "The maximal GDNF expression of PEI600-g-CHI/DNA was at the polymer:DNA weight ratio of 10:1, which was 1.7-fold higher than the maximal GDNF expression of PEI1800-g-CHI/DNA. The low toxicity and high transfection efficiency of PEI600-g-CHI make it ideal for application to GDNF gene therapy, which has potential for the treatment of Parkinson's disease."

Journal • Biosimilar • Parkinson's Disease

UniQure: Annual Report 2014 (UniQure) - Anticipated expiry of patents in US in 2015 and 2017; Anticipated expiry of method of manufacturing patents in US, Japan, Europe and other jurisdictions in 2028

Anticipated patent expiry • Parkinson's Disease

Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions. (PubMed) - "Sulfs introduce dynamic changes in HS proteoglycan sulfation patterns of the postnatal cerebellum, thereby orchestrating fundamental mechanisms underlying brain development."

Journal • Biosimilar

DEMYELINATION/REMYELINATION AND EXPRESSION OF INTERLEUKIN-1β, SUBSTANCE P, NERVE GROWTH FACTOR, AND GLIAL-DERIVED NEUROTROPHIC FACTOR DURING TRIGEMINAL NEUROPATHIC PAIN IN RATS. (PubMed) - Neurosci Lett - "IL-1β may have effects both in ganglia and nerves, while SP may be an important mediator at the nerve endings. Additionally, low levels of GDNF may produce impaired signaling, which may be involved in generation of pain."

Journal • Biosimilar • Pain

Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis. (PubMed) - Hum Mol Genet - "Yet, ablation of TNFR1 completely abolished GDNF rises in both SOD1(G93A) astrocytes and spinal cords, a condition that accelerated motor neuron degeneration and disease progression. Our data suggest that the astrocytic TNFR1-GDNF axis represents a novel target for therapeutic intervention in ALS."

Journal • Biosimilar • Complement-mediated Rare Disorders • Pain

Plasma glial cell line-derived neurotrophic factor in patients with major depressive disorder: a preliminary study. (PubMed) - "Our findings revealed significantly lower plasma GDNF level in recurrent-episode MDD patients, although plasma GDNF levels in MDD patients and healthy controls did not differ significantly. The discrepancy between our study and previous studies might arise from differences in the recurrence of depression or the ages of the MDD patients."

Journal • Biosimilar

GDNF-Induced cerebelllar toxicity: A brief Review. (PubMed) - Neurotoxicology - "While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed."

Journal • Review • Biosimilar • Parkinson's Disease

Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease. (PubMed) - "Moreover, naringin could attenuate the level of tumor necrosis factor-α in microglia increased by MPP(+)-induced neurotoxicity in the substantia nigra. These results indicate that naringin could impart to DA neurons the important ability to produce GDNF as a therapeutic agent against PD with anti-inflammatory effects, suggesting that naringin is a beneficial natural product for the prevention of DA degeneration in the adult brain."

Journal • Parkinson's Disease

Gut Hormone, Nociceptors, Neurotrophic Factors Expression in Functional Dyspepsia (clinicaltrials.gov) - P=N/A; N=314; Completed; Sponsor: Seoul National University Bundang Hospital; Recruiting -> Completed ; Trial primary completion date: Jul 2015 ->Jun 2014

Trial completion • Trial primary completion date • Biosimilar • Immunology • Inflammation