Brain-derived neurotrophic factor (BDNF) is a neurotrophin of marked commercial, scientific, diagnostic, and therapeutic interest. The preservation of its structural cystine-knot is the main challenge in its industrial production. A suitable expression system is critical to achieve the most efficient production of bioactive and stable BDNF for pharmaceutical purposes.

01 May 2024·International Journal of Biological Macromolecules

Functional modification of recombinant brain-derived neurotrophic factor and its protective effect against neurotoxicity

Article

Author: Xie, Yining ; Liu, Chang ; Chen, Chen ; Zheng, Qian ; Yan, Qi ; Zhao, Meijun ; Yang, Huiying ; Ding, Xuying

Brain-derived neurotrophic factor (BDNF) is a neurotrophic protein that promotes neuronal survival, increases neurotransmitter synthesis, and has potential therapeutic effects in neurodegenerative and psychiatric diseases, but its drug development has been limited by the fact that recombinant proteins of BDNF are unstable and do not penetrate the blood-brain barrier (BBB). In this study, we fused a TAT membrane-penetrating peptide with BDNF to express a recombinant protein (TBDNF), which was then PEG-modified to P-TBDNF. Protein characterization showed that P-TBDNF significantly improved the stability of the recombinant protein and possessed the ability to penetrate the BBB, and in cellular experiments, P-TBDNF prevented MPTP-induced nerve cell oxidative stress damage, apoptosis and inflammatory response, and its mechanism of action was closely related to the activation of tyrosine kinase B (TrkB) receptor and inhibition of microglia activation. In animal experiments, P-TBDNF improved motor and cognitive deficits in MPTP mice and inhibited pathological changes in Parkinson's disease (PD). In conclusion, this paper is expected to reveal the mechanism of action of P-TBDNF in inhibiting neurotoxicity, provide a new way for treating PD, and lay the foundation for the future development of recombinant P-TBDNF.

27 Feb 2024·ACS Nano

Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor–Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel

Article

Author: Li, Yang ; Chen, Kuntao ; Gong, Shusheng ; Liu, Shengnan ; Yin, Lan ; Yu, Qianru ; Jiang, Dan ; Liu, Ke ; Guo, Rui

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

News (Medical) associated with Brain-derived neurotrophic factor(The Max Planck Institute)

27 Oct 2021

·www.biospace.com

Otonomy Announces Multiple Presentations at Neuroscience 2021 Meeting

Presentation of positive top-line clinical results for OTO-313 in tinnitus and OTO-413 in hearing loss Supportive preclinical data to be presented for OTO-825 gene therapy and OTO-510 otoprotection program SAN DIEGO, Oct. 27, 2021 (GLOBE NEWSWIRE) -- Otonomy, Inc. (Nasdaq: OTIC), a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology, today announced multiple presentations at the upcoming Neuroscience 2021 meeting, which is the annual meeting of the Society for Neuroscience (SfN). This meeting will be held virtually November 8-11, 2021 with Preview Days taking place November 3-7 during which registered attendees can preview pre-recorded presentations. Otonomy’s presentations include the previously disclosed positive top-line clinical results for OTO-313 in tinnitus and OTO-413 in hearing loss, and multiple presentations related to Otonomy’s preclinical programs. “We are pleased to have the opportunity to review the positive clinical results for OTO-313 and OTO-413 for the broader neuroscience research community during this prestigious conference,” said Alan C. Foster, Ph.D., chief scientific officer of Otonomy. “Our multiple presentations highlight the breadth of our pipeline and provide supportive data for our preclinical programs including OTO-825, a gene therapy for congenital hearing loss, and OTO-510, an otoprotectant for cisplatin-induced hearing loss.” The following presentations related to Otonomy’s clinical programs will be held during interactive poster sessions occurring from 3:15 to 4:15 p.m. EST on November 8. “Initial clinical evaluation of OTO-313 given as a single intratympanic injection in patients with moderate to severe, persistent tinnitus” by Anderson et al. “A first-in-human study of OTO-413, an intratympanic sustained-exposure formulation of BDNF, for the treatment of hearing loss” presented by Victoria Sanchez, Au.D., Ph.D., Assistant Professor of University of South Florida and principal investigator on the study. All other Otonomy presentations are during interactive poster sessions occurring from 3:30 to 4:30 p.m. EST on November 10. “AAV-mediated gene therapy with OTO-825 rescues hearing loss and cochlear degeneration in two mouse models of GJB2 congenital hearing loss” a joint presentation from Otonomy and Applied Genetics Technology Corporation (AGTC) by Uribe et al. “Local delivery of BDNF (OTO-413) and a selective TrkB agonist (M3) restores hearing function in models of cochlear synaptopathy” by Fernandez et al. “Identification and characterization of OTO-510 as a novel approach to the prevention of cisplatin-induced hearing loss” by Mathur et al. “Novel fab fragments derived from Trk-selective agonist monoclonal antibodies are potent and selective antagonists of the TrkB and TrkC receptors” by Siegel et al. About Otonomy Otonomy is a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology. The company pioneered the application of drug delivery technology to the ear in order to develop products that achieve sustained drug exposure from a single local administration. This approach is covered by a broad patent estate and is being utilized to develop a pipeline of products addressing important unmet medical needs including Ménière’s disease, hearing loss, and tinnitus. For additional information please visit . Contacts: Media Inquiries: Spectrum Science Chloé-Anne Ramsey Vice President 404.865.3601 cramsey@spectrumscience.com Investor Inquiries: Westwicke ICR Robert H. Uhl Managing Director 858.356.5932 robert.uhl@westwicke.com

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100 Deals associated with Brain-derived neurotrophic factor(The Max Planck Institute)

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Indication	Highest Phase	Country/Location	Organization	Date
Amyotrophic Lateral Sclerosis	Phase 2	-	Regeneron Pharmaceuticals, Inc.	-
Amyotrophic Lateral Sclerosis	Phase 2	-	Amgen, Inc.	-
Amyotrophic Lateral Sclerosis	Phase 2	-	Sumitomo Pharma Co., Ltd.	-
Amyotrophic Lateral Sclerosis	Phase 2	-	The Max Planck Institute	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ISC2019	Not Applicable	Brain-derived neurotrophic factor (BDNF)	-	Brain-derived Neurotrophic Factor (High-salt diet)	(batvlypgxc) = iovcugbnpr htyhrjnzvp (bfwvijpzsl ) View more	-	01 Feb 2019
				Continuous intracerebroventricular injection of BDNF	evehvwtzet(wrceaurzfq) = ihrtlirshd uglqrommnz (vdjeduhqim ) View more
ARVO2018	Not Applicable	-	-	BDNF (661W cone photoreceptor cells)	iytanqlhmb(tmkituazyg) = vnzbrrvrwv olkvofegtu (ngmbdprmkp ) View more	-	01 Jul 2018
				BDNF (SHSY5Y sensory neurons)	qknnbaxpvl(jqhhuuarpj) = hkyoegcgnc svogioctmv (rybdqnfutt ) View more
ARVO2011	Not Applicable	Optic Nerve Injuries	-	Brilliant Blue G	zbffhpaxac(sbyjgrgftj) = xnbyihzwyj mmdpghivww (fwkylqnzpm ) View more	-	01 Apr 2011
				Vehicle (0.9% NaCl)	(vuxlhhmdqz) = uksmowoaid trxtfifffz (dtcswbhvtf )
ARVO2010	Not Applicable	BDNF	-	BDNF-PLGA microspheres	(eqsdcnhdor) = ylvemfskvq gpdwbpdmxs (mtkwzqamwh, 3.4) View more	Positive	01 Apr 2010
				Blank PLGA microspheres	(eqsdcnhdor) = aiwemerkhz gpdwbpdmxs (mtkwzqamwh, 2.1) View more
ARVO2005	Not Applicable	-	-	Vehicle	(jgntlspnwk) = zxndroyynn issptvdyxb (ljxessgejn )	-	01 May 2005
				BDNF	(jgntlspnwk) = smhvkbmdkt issptvdyxb (ljxessgejn )
ARVO2003	Not Applicable	Ganglion Cysts	-	Adenosine 10 µM	rplwrliasm(scainrenux) = hcgufxsxhh ncejtfwjmn (uqjjbmrckt )	-	01 May 2003
				Adenosine 100 µM	rplwrliasm(scainrenux) = mkzexsujxw ncejtfwjmn (uqjjbmrckt )

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