Treating Untreatable Retinal and Optic Nerve Conditions - The Stem Cell Ophthalmology Treatment Studies

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1 Treating Untreatable Retinal and Optic Nerve Conditions - The Stem Cell Ophthalmology Treatment Studies Jeffrey N. Weiss, M.D. President, Healing Institute Margate, Florida

2 SCOTS I/II Institutional Review Board Approved Registered with NIH NCT NCT

3 What Eye Diseases Are Eligible for Treatment? Retinal Eye Diseases that are progressive, otherwise untreatable or may lead to blindness. Optic Nerve Diseases that are progressive, otherwise untreatable or may lead to blindness.

4 Potential Retinal Diseases Retinal Diseases: Age Related Macular Degeneration (AMD) Hereditary Retinopathies such as Retinitis Pigmentosa (RP), Stargardt s Disease, Cone- Rod Dystrophy and other less common conditions Myopic Macular Degeneration Vascular Diseases including Diabetic Retinopathy Damage from prior Retinal Detachment Others if they fit criteria

5 Normal Eye- Posterior Pole

6 Age-related Macular Degeneration

7 Stargardt s Disease

8 Myopic Macular Degeneration

9 Retinitis Pigmentosa

10 Potential Optic Nerve Diseases Glaucoma Ischemic Optic Neuropathy Optic Atrophy Optic Neuropathy Some Optic Nerve Trauma Others if they fit our criteria

11 Normal Eye - Optic Nerve

12 Optic Nerve Atrophy

13 Optic Nerve- Glaucoma

14 Visual Field Loss

15 54 y.o female R eye suddenly lost vision upon arising 6/6/10 R 20/400 with superior altitudinal VF defect L 20/30 with superotemporal and inferonasal VF defects R second attack 10/10: lost the inferonasal VF R third attack 1/11: lost inferotemporal VF L attack 6/11: 20/70 with deeper defects than before

16 June 2011 Work-up Stepwise Visual Loss: R 3 attacks in 1 year, L two attacks from 6/6/10-6/11 Review prior records from OD (exam 5/10 had been 20/20 OU) Exam: R 20/400 eccentric, L 20/70, R MG pupil No proptosis, no motility abnormality, no retinopathy VF: R almost zero in central 30-2, L SupTemp & InfNas OCT: both in worst 1%ile/age: avg RNFL R 37.43, L Blood work for auto-immune disorders ordered: -ANA, ACE, lysozyme, RPR, Lyme s, NMO, paraneoplastic, microsomal Ab

17 Oregon: Anti-Optic Nerve Antibodies 8/8/ /12/2011 Documentation of Pathogenetic Antibodies can help patients qualify for expensive therapies.

18 L 20/70 and R CF pre-op Not driving Above: L and R Humphrey VF in Margate, FL pre-op 11/4/13, Below 3m postop 2/5/14 Ohio L 20/15 and R 20/200 eccentric 3 mos post-op Driving day & night

19 Second Optic Neuropathy Patient 23WF hair colorist and youngest in salon (cleans up, many chemicals) January 2013: sudden hand and arm numbness, flushing, numbness around mouth while driving MRI: Chiari malformation (8mm) Feb-March: New daily headaches: OP 32, 26.5, Diamox April-June: losing central vision OU to bare LP 6/17/13: bilateral optic nerve sheath decompression to regain peripheral vision Blood test for Leber s: positive 3460

20 1 month postop Vitrectomy and injection into L nerve, shunt vessels at 4:00 near center don t leak

21 L=HM R=HM Above: Pre rx L and R Goldmann VF on 12/4/13 Below: Post rx at 1 month 1/21/14 L and R L=J 20/800 R= CF 360

22 27 YEAR OLD FEMALE 2009, decreased vision OU with pain on eye movement Disc edema OU, temporal pallor OU Dx d with idiopathic optic neuritis/optic atrophy OU /400 (20/1600) OD, 5/700 (20/2800) OS /225 (20/900 (OD), 5/300 (20/1200) OS 2014 Wilmer Eye Institute 5/200 OD, 1/200 OS 3/2014 Arm 3 OS (vitrectomy) Arm 2 OD 6/2014 5/300 OD, 20/40-2 OS 8/2014 Wilmer Eye Institute 20/100+1 OD, 20/40-2 OS Visual Field Improvement OU

23 Glaucoma 84 year old male, 20 year hx of COAG S/P trab OU, max med rx, IOP OD/OS 20 OD CF 6, ETDRS 5/200-3, OS LP 6 weeks post Arm 2 OD 20/200, ETDRS 20/100-2, OS HM, IOP OD/OS 7/8 OCT OD 135 to 338 microns

24 Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) Ischemic, non-inflammatory process per 100,000 population (U.S.) Mean age of occurrence years of age Painless loss of vision, over hours to days Progressive form 22% - 37% of cases

25 NAION Most cases idiopathic, (radiation, hypotension) 55% - 80%, altitudinal, generally inferior visual field loss Vision generally stable 2 months after initial incident VA </=20/64, 52% of patients were 20/200 or worse at 6 mos. Second eye involvement, 14.7% median of 5 years Risk factors for 2 nd eye, VA 20/200 or worse/diabetes

26 NAION- Cause? Thrombosis? Axonal swelling leads to compartment syndrome? Crowded or disc at risk optic nerve head Compromise of posterior ciliary circulation

27 NAION Inner retinal layer atrophy with preservation of RNFL and GCL even in NLP eyes Cannot equate optic disc pallor with visual function Treatment includes: anticoagulants, diphyenylhydantoin, atropine, steroids, vasodilators, optic nerve sheath decompression None proven beneficial

28 NAION 10 patients Average age 69.8 years History NAION from 1 35 years (average 9.8)

29 RESULTS 80% Improved Snellen binocular vision 20% Stable 73.6% of eyes gained vision 15.9% Stable Average 3.53 Snellen lines improvement Statistically significant results.

30 LEBER S HEREDITARY OPTIC NEUROPATHY (LHON) Mitochondrial disorder-death of retinal ganglion cells Mutations G11778A/MT-ND4 gene G3460A/MT-ND1 gene 14484T>C/MT-ND6 gene Variability in expressiveness - 50% males, 10% females with above mutations develop optic atrophy Increased oxidative stress and apoptosis

31 LHON Visual Loss Early adulthood Cloudy vision one or both eyes Interval between visual loss, days months Spontaneous improvement within 6 12 months after visual loss has been reported (11778 mutation)

32 NO PROVEN TREATMENT Therapy to reduce oxidative stress and to increase mitochondrial respiration. Vitamins, Cofactors - Coenzyme Q 10, folic acid, vitamin B12, riboflavin, L-carnitine, creatinine Electron acceptors, vitamin C Free radical scavengers, idebenone, EPI-743, alpha lipoic acid, curcumin, vitamin E Inhibitors of toxic metabolites, dicholoroacetate Customized treatments

33 LHON 5 PATIENTS TREATED 1. PRE CF1, NLP 6M P-OP CF2, NLP 2. PRE HM2, HM2 12M P-OP CF7, 20/ PRE NLP, HM -- 9M P-OP NLP, 20/ PRE CF6, CF6 7M P-OP 20/100, 20/ PRE 6/270, 6/270 (20/1000) 8M P-OP 6/240 (20/800), 6/210 (20/700)

34 LHON 1 ST report of BMF showing benefit in hereditary mitochondrial disease Mitochondrial Transfer Mechanism A. exosomes providing microrna B. Growth factors C. Paracrine effects D. Transdifferentiation

35 Serpiginous choroidopathy Rare clinical entity causing less than 5% of posterior uveitis cases. It has a higher prevalence in men and affects young to middleaged adults. No systemic disease associations have been identified. SC is a challenging disease, probably autoimmune in origin and frequently managed with corticosteroids and other immunosupressants.

36 Serpiginous choroidopathy

37 Serpiginous Choroidopathy 77 year old male with 20/80- OD, 20/50- OS Arm 2 OU 2 weeks postop. 20/60+1 OD, 20/20-3 OS 8 months postop. 20/60+1 OD, 20/25-3 OS Regained driver s license RNFL thickening by OCT OU

38 Dominant Optic Atrophy 6 patients 5 patients Arm 2 OU 1 patient Arm 2/3 83.3% of patients improved OU 10 eyes median improvement 2.12 Snellen lines, 10.6 letters

39 Retinitis Pigmentosa 17 patients/33 eyes treated 11 patients (65%) improved, Snellen lines improvement 8 patients (35%) stable

40 Retinitis Pigmentosa 33 eyes 15 eyes (45.5%) improved 7.9 Snellen lines 15 eyes (45.5%) stable 3 eyes (9%) worsened, average of 1.7 Snellen lines Improvements 1 27 lines of vision Statistically significant

41 Retinitis Pigmentosa Logmar Scale Improvement 23% - 90% (average 41% improvement over baseline acuity) No surgical complications

42 Usher Syndrome Retinitis Pigmentosa/Hearing loss 10 patients Visual Improvement 80% of eyes Average increase in visual acuity 36.4% Logmar in eyes that exhibited improvement P <.001.

43 Stargardts Disease 17 patients, 34 treated eyes 18 (53%) improved 11(32%) Stable 5 (15%) Worsened No surgical complications

44 Inclusion Criteria Must have 20/40 or worse vision in one or both eyes. And / Or visual field damage. Potential for response to stem cells. Ability to safely undergo the procedure.

45 Exclusion Criteria Pregnant Inability to undergo the procedure safely Significant medical problems Unlikelihood of response to BMF Architecture of eye not normal

46 General Outline of Procedure MAC/Sedation - Anesthesia Bone Marrow Aspiration/Harvesting Separation of Stem Cells from Bone Marrow using FDA approved device Injection of BMF including Intravenous Recovery and Follow up Day 1 Additional reports at 1 month, 3 months, 6 months and 12 months post procedure

47 3 TREATMENT ARMS Arm 1- Retrobulbar and Subtenons, both eyes + Intravenous Arm 2- Retrobulbar, Subtenons, Intravitreal, both eyes + Intravenous Arm 3- Retrobulbar, Subtenons, Intravitreal in better eye / Vitrectomy and Intraocular worse eye + Intravenous

57 Goals Will provide clinical data on which eye diseases at what stages are most responsive to BMF treatment. Ultimate goal is to have BMF treatments become a standard part of the care of certain eye diseases to prevent blindness.

58 REFERENCES 1. Weiss JN, Levy S. The Role of Patient Funded Clinical Research in Advancing Medical Care. ClinicalTrials.gov Identifier: NCT Weiss JN, Levy S, Malkin A. Stem Cell Ophthalmology Treatment Study (SCOTS) for Retinal and Optic Nerve Disease: a Preliminary Report. Neural Regeneration Research. 10;6: , Weiss JN, Levy S, Benes SC. Stem Cell Ophthalmology Treatment Study (SCOTS) for Retina and Optic Nerve Disease: Case Report of Improvement in Relapsing Auto-Immune Optic Neuropathy. Neural Regeneration Research. 10;9: , Weiss JN, Levy S, Benes, SC. Stem Cell Ophthalmology Treatment Study (SCOTS): Bone Marrow Derived Stem Cells in the Treatment of Leber Hereditary Optic Neuropathy. Neural Regeneration Research. 11: , Weiss JN, Levy S, Benes, SC. Stem Cell Ophthalmology Treatment Study (SCOTS) Improvement in Serpiginous Choroidopathy Following Autologous Bone Marrow Derived Stem Cells. Neural Regeneration Research. 11: , 2016.

59 REFERENCES 6. Weiss JN, Levy S. Neurologic Stem Cell Treatment Study (NEST) using bone marrow derived stem cells for the treatment of neurological disorders and injuries: study protocol for a nonrandomized efficacy trial. Clin Transl Degener Dis. 12;1(4): , Weiss JN, Benes SC, Levy S. Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of non-arteritic ischemic neuropathy (NAION). Stem Cell Investigation. November Weiss JN, Levy S. Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of Retinitis Pigmentosa. June

60 THANK YOU QUESTIONS? Jeffrey Weiss, M.D

61 NEUROLOGIC BONE MARROW FRACTION TREATMENT Jeffrey N. Weiss, M.D. President, Healing Institute Margate, Florida

62 Conditions Treated Stroke (CVA) Traumatic Brain Injury (TBI) Chronic Multiple Sclerosis (MS) Parkinson s Disease Diabetic Neuropathy

63 Procedure Bone Marrow Aspiration Separation of Bone Marrow Fraction IV infusion Intranasal application - Aerosol

66 Cribriform Plate Primary Olfactory Nerves 40 openings primary olfactory sensory neurons enter CNS synapse with secondary neurons olfactory bulb continuing as olfactory nerve Olfactory stem cells basal cells

67 Treatment Eligibility Functional damage unlikely to improve with standard of care At least 6 months post disease onset Stable on current medical therapy Potential for improvement Minimal risk of potential harm medically stable

68 Preoperative UPDRS scale for Parkinson s Disease EDSS for Multiple Sclerosis Neuropsych. Evaluation for Traumatic Brain Injury

69 Procedure 2 Treatment arms Arm 1 IV approximately 15 cc BMF Arm 2 IV and inhalation

70 Follow-up Neurologic Assessment: 1 day 1 month 3 months 6 months 1 year

71 Stem Cell Spinal Cord Injury Exoskeleton and Virtual Reality SciExVR Treatment Study IRB approved Clinicaltrials.gov Identifier: NCT

72 SciExVR Treating spinal cord injury Bilateral paraspinal injections of autologous bone marrow derived stem cells + IV and Intranasal 3 Arms, including Exoskeleton and Virtual Reality Device

73 SciExVR Follow-up examinations: 1, 3, 6,12 months American Spinal Injury Association (ASIA) Impairment Scale (AIS) used to classify degree of spinal cord injury by assessing motor and sensory function.

74 REFERENCES 1. Weiss JN, Levy S. The Role of Patient Funded Clinical Research in Advancing Medical Care. ClinicalTrials.gov Identifier: NCT Weiss JN, Levy S, Malkin A. Stem Cell Ophthalmology Treatment Study (SCOTS) for Retinal and Optic Nerve Disease: a Preliminary Report. Neural Regeneration Research. 10;6: , Weiss JN, Levy S, Benes SC. Stem Cell Ophthalmology Treatment Study (SCOTS) for Retina and Optic Nerve Disease: Case Report of Improvement in Relapsing Auto-Immune Optic Neuropathy. Neural Regeneration Research. 10;9: , Weiss JN, Levy S, Benes, SC. Stem Cell Ophthalmology Treatment Study (SCOTS): Bone Marrow Derived Stem Cells in the Treatment of Leber Hereditary Optic Neuropathy. Neural Regeneration Research. 11: , Weiss JN, Levy S, Benes, SC. Stem Cell Ophthalmology Treatment Study (SCOTS) Improvement in Serpiginous Choroidopathy Following Autologous Bone Marrow Derived Stem Cells. Neural Regeneration Research. 11: , 2016.

75 REFERENCES 6. Weiss JN, Levy S. Neurologic Stem Cell Treatment Study (NEST) using bone marrow derived stem cells for the treatment of neurological disorders and injuries: study protocol for a nonrandomized efficacy trial. Clin Transl Degener Dis. 12;1(4): , Weiss JN, Benes SC, Levy S. Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of non-arteritic ischemic neuropathy (NAION). Stem Cell Investigation. November Weiss JN, Levy S. Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of Retinitis Pigmentosa. June

76 THANK YOU

Non-arteritic anterior ischemic optic neuropathy (NAION) with segmental optic disc edema. Jonathan A. Micieli, MD Valérie Biousse, MD

Non-arteritic anterior ischemic optic neuropathy (NAION) with segmental optic disc edema Jonathan A. Micieli, MD Valérie Biousse, MD A 75 year old white woman lost vision in the inferior part of her visual