Slide 1: MANF: A novel neurotrophic factor for retinal disorders
1 Mesencephalic Astrocyte - derived Neurotrophic Factor (MANF) A novel neurotrophic factor with potential for treatment of retinal disorders OTCQB : AMBS Targeting Ocular Disorders 2014 1
Slide 2: Forward-Looking Statements
2 This presentation contains “forward - looking statements” within the meaning of the “safe - harbor” provisions of the Private Securities Litigation Reform Act of 1995. Such statements involve known and unknown risks, uncertainties and other factors that could cause the actual results of the Compan
Slide 3: MANF: A Novel Growth Factor
MANF: A Novel Growth Factor » MANF: Mesencephalic astrocyte - derived neurotrophic factor » Original discovery by Amarantus’ CSO » Prototype of emerging family of novel growth factors » Evolutionary highly conserved structure and function » Expressed in response to cellular stress » Cell protective
Slide 4: From Astrocytes to DA Neurons to the Retina
From Astrocytes to DA Neurons to the Retina » Astrocytes were the initial source for MANF discovery » MANF supports survival of dopaminergic neurons » MANF expression in the retina peaks at P10 » MANF expression steadily decreases as the retina matures » Re - activation of developmental genes observ
Slide 5: Structure and Function is Evolutionally Highly Conserved
MANF Structure and Function is Evolutionally Highly Conserved » Sequence is highly conserved from human to fruit - fly to nematode » Human MANF can compensate the function of fruit - fly MANF » MANF acts through an evolutionally conserved pathway » High probability of translational success from anim
Slide 6: Prevents Stress-induced Apoptosis
MANF Prevents Stress - induced Apoptosis 6 MANF promoter contains ER stress response element MANF expression is induced by ER stressors ER stress ( Tunicamycin ) Primary neurons Apoptosis – TUNEL + MANF prevents ER stress - induced apoptosis Reduction of TUNEL + cells Figures from Tadimalla et al.,
Slide 7: Potential Therapeutic Areas
MANF Potential Therapeutic Areas 7 MANF Ophthalmology Neurology Diabetes Cardiovascular Retinitis Pigmentosa Optic Nerve Ischemia (CRAO, CRVO) Glaucoma
Slide 8: Retinitis Pigmentosa
Retinitis Pigmentosa » Genetic disease of the retina x 1:3500 subjects; Est. China 400k, US 100k, EU 100k, JP 50k x No treatment currently approved » Progressive vision loss x Rod photoreceptors followed by cone degeneration x Night vision loss followed by loss of peripheral vision x Progression to
Slide 9: Protects Photoreceptors in the RP Model S334ter Line
MANF Protects Photoreceptors in the RP Model S334ter Line 3 » Rhodopsin termination mutation at position 334 » Protein aggregation, unfolded protein response, apoptosis » Primary rod photoreceptor degeneration » Secondary cone degeneration » Single MANF admin on Day 9 for rod protection » Single MAN
Slide 10: Protects the Retina in two Additional Models of RP
MANF Protects the Retina in two Additional Models of RP 10 MANF protects photoreceptors against apoptosis MANF preserves photoreceptors in the outer nuclear layer of the retina » Photoreceptor - specific transcription factor (CRX: cone - rod homeobox ) » Controls expression of retinal genes ( rhodop
Slide 11: Functional Protective Effect of MANF in an Optic Nerve Ischemia Model
Functional Protective Effect of MANF in an Optic Nerve Ischemia Model – CRAO/CRVO/Glaucoma » Retinal ischemia is a cause of visual impairment and blindness » Occlusion / reperfusion model x Central retinal artery occlusion (CRAO) x Central retinal vein occlusion (CRVO, orphan) x Glaucoma » Single in
Slide 12: Protects Retinal Cells from Injury
MANF Protects Retinal Cells from Injury 12 Photoreceptors S334ter, crx , rd1 Retinitis Pigmentosa Mueller Glia ERG data CRAO, CRVO, glaucoma Retinal Ganglion Cells Nerve crush model Glaucoma MANF exhibits broad protective activity in retinal injury models
Slide 13: Safety Data
MANF Safety Data » Single MANF admin by intravitreal injection to pigmented rabbits » Dose level scaled from highest rat ONI dose to rabbit vitreous volume » Adequate number of animals for pilot ocular tolerance study » 15 - day follow - up x Split lamp examination (McDonald - Shadduck’s scale) x Ge
Slide 14: Summary
MANF Summary » Protein drug with breakthrough biology » Conserved structure and biology » Counteracts cellular stress » Prevents retinal degeneration in models of retinitis pigmentosa » Provides functional benefit in optic nerve ischemia model » Safe and well tolerated in pilot ocular tolerance stud