Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling

Abstract

Previous studies have demonstrated that intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury. BDNF gene therapy can improve RGC survival in experimental models of glaucoma, the leading cause of irreversible blindness worldwide. However, the therapeutic efficacy of BDNF supplementation alone is time limited at least in part due to BDNF receptor downregulation. Tropomyosin-related receptor kinase-B (TrkB) downregulation has been reported in many neurological diseases including glaucoma, potentially limiting the effect of sustained or repeated BDNF delivery.Here, we characterize a novel adeno-associated virus (AAV) gene therapy (AAV2 TrkB-2A-mBDNF) that not only increases BDNF production but also improves long-term neuroprotective signaling by increasing expression of the BDNF receptor (TrkB) within the inner retina. This approach leads to significant and sustained elevation of survival signaling pathways ERK and AKT within RGCs over 6 months and avoids the receptor downregulation which we observe with treatment with AAV2 BDNF alone. We validate the neuroprotective efficacy of AAV2 TrkB-2A-mBDNF in a mouse model of optic nerve injury, where it outperforms conventional AAV2 BDNF or AAV2 TrkB therapy, before showing powerful proof of concept neuroprotection of RGCs and axons in a rat model of chronic intraocular pressure (IOP) elevation. We also show that there are no adverse effects of the vector on retinal structure or function as assessed by histology and electroretinography in young or aged animals. Further studies are underway to explore the potential of this vector as a candidate for progression into clinical studies to protect RGCs in patients with glaucoma and progressive visual loss despite conventional IOP-lowering treatment.

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

“…This approach when delivered to retinal ganglion cells via an AAV2 vector yielded functional proteins which demonstrated neuroprotection in both optic nerve crush and experimental glaucoma models. 54 It is conceivable that combining two or more transgenes coding for proteins targeting multiple pathways related to glaucoma pathogenesis could provide an effective approach to deliver targeted, sustained and individualised treatment to maximise efficacy. We have also discussed the use of CRISPR/Cas9 as a gene-editing tool for glaucoma elsewhere 97 and other gene and post-translation modification approaches to modify ocular disease have been extensively reviewed.…”

Trockene AMD – zelluläre und gentherapeutische Behandlungsansätze

“…Darüber hinaus ist ein Austausch der PEDF-Gensequenz gegen andere neuroprotektiv wirksame Faktoren, wie der Brain-derived Neurotrophic Factor (BDNF) oder der Glial-derived Neurotrophic Factor (GDNF) denkbar. Der Faktor BDNF ist das am häufigsten vorkommende Neurotrophin im zentralen Nervensystem und seine protektive Wirkung auf retinale Ganglienzellen konnte in verschiedenen Schädigungsmodellen nachgewiesen werden [50,51]. Der Faktor GDNF gilt als aussichtsreicher Kandidat für die Behandlung von Parkinson [52]; seine protektive Wirkung im Auge wurde u. a. durch eine verlangsamte retinale Degeneration belegt [53].…”

Contribution at the Study of Neuroprotective Properties of Neuroglobin during Severe Chronic Glaucoma

“…However, although this approach is effective for many patients with glaucoma, a significant proportion of their visual function deteriorates inexorably. In fact, about one in eight patients with glaucoma become blind in at least one eye despite this treatment [6] [21]. In animals, experimental therapies targeting and protecting retinal ganglion cells against phenomena related to hypoperfusion of the optic nerve (ischemia, hypoxia, oxidative stress, apoptosis) have been evoked and grouped under the term neuroprotection [6] [22]- [27].…”

“…In fact, about one in eight patients with glaucoma become blind in at least one eye despite this treatment [6] [21]. In animals, experimental therapies targeting and protecting retinal ganglion cells against phenomena related to hypoperfusion of the optic nerve (ischemia, hypoxia, oxidative stress, apoptosis) have been evoked and grouped under the term neuroprotection [6] [22]- [27]. Considered as neuroprotective molecule, neuroglobin (Ngb) is a protein belonging to the family of human globins [28]- [37].…”