Titel einfgen

Univ.Doz.Dr.med. Georg S. Kobinia

STEM CELL THERAPY

Point-of-Care Stem cell TherapyAutologous bone marrow-derived stem cells transplant with on-site cell concentration for nonmalignant diseases.

What is a Stem Cell?It can replicate itself (renewal)It can give rise to more specialized cells (differentiation).Stem cells reside in organs and tissues throughout the body and help replace old, worn or damaged cells. They are the bodys biological repair kit.Stem cells can give rise to a wide variety of specialized cells, including heart cells, blood cells, liver cells, and neurons.

Bone Marrow-derived mononuclear cells (BM-MNCs)

Cellular mechanism (Plasticity)

Paracrine effect (Plasma is important adjuvant)

Secretomes (released after cell death)Mechanisms of action231

No rejection (GvHD) of the graft.Stem cells are always available.In contrast to embryonic cells no risk of cancer, no ethical concerns, fewer regulatory problems.

Autologous

6

SepaxFully-automated, mobile system

Efficient and reproducible processing of bone marrow, umbilical cord blood or peripheral blood

POINT OF CARE

1. Aktas M, Radke TF, Strauer BE, Wernet P, Kogler G. Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax. Cytotherapy. 2008;10(2):20311.

Sepax 2 Mononuclear cells, MNCPlasma

MINIMAL CELL MANIPULATION

TreatmentsNeuron Point-of-care Stem Cell Therapy.Amyotrophic lateral sclerosis, cerebral palsy, spinal cord injury, stroke, autism.Cardiac Point-of-care Stem Cell Therapy.Cardiomyopathy.Derma Point-of-care Stem Cell Therapy.Non-healing wound, In battle field transplantations.Septic woundsVascular Point-of-care Stem Cell Therapy.Critical limb ischemia, peripheral artery disease.Endocrine Point-of-care Stem Cell Therapy.Type 1 diabetes.Ortho Point-of-care Stem Cell Therapy.Non-traumatic osteonecrosis.Osteoarthritis.Septic fracture.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis 85 patients

Amyotrophic lateral sclerosis

Cerebral Palsy

Pilot clinical study in 80 patients

39 patients had also epilepsy.

16 patients had a related stroke.

24 of them had an structural defect.

Cerebral PalsyDeclaration of Helsinki Ethical principles / Unproven Interventions in Clinical PracticeMean age 6,4 years old, 65% men and 35% women

1. Palisano et al. 1997. 2. Eliasson et al. 2006. 3. Reid, Johnson, and Reddihough 2010. 4. Pennington et al. 2013. 5. Hidecker et al. 2011. 55% of the patients had a better

Cerebral Palsy

90% of the patients had a subjective improvement71% in spasticity.71% in motoric.63% in coordination.18% in speech.14% in communicative or cognitive symptoms.5% in the frequency of epileptic attacks.

No changes were found in EEG and MRI

Cerebral Palsy

Cerebral Palsy

Cerebral Palsy

AUTISM

Brain Injury

Cox CS, Baumgartner JE Jr, Harting MT et al (2011) Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery 68:588600Tian, C., Wang, X., Wang, X., Wang, L., Wang, X., Wu, S., Wan, Z., 2013. Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp. Clin. Transplant. Off. J. Middle East Soc. Organ Transplant. 11, 176181. doi:10.6002/ect.2012.0053

(Cox et al. 2005)

BMN MSC- Open label study in adults with sub acute Subacute sever TBI (N=97) 38 of 97 patients (39.2%)HSC autolog (1 month) TBI; follow up 15 days. 1 106 cells/mL (5 ml.) with TBI improved. Eleven of 24 patients (45.8%) with persistent vegetative state showed post therapeutic improvements in consciousness (P = .024)

(Tian et al. 2013)

Spinal Cord Injury

Park DH, Eve DJ, Chung YG, Sanberg PR (2010) Regenerative medicine for neurological disorders. ScientificWorldJ 10:470489Sykova E, Homola A, Mazanec R et al (2006) Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15:675687

(Park et al. 2005)(Sykova et al. 2006)

Spinal Cord Injury

Yoon SH, Shim YS, Park YH et al (2007) Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: phase I/II clinical trial. Stem Cells 25:20662073.Geffner LF, Santacruz P, Izurieta M et al (2008) Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant 17:12771293

(Yoon et al. 2007)

(Geffner et al. 2008)ACUTE VS. CHRONIC ADMINISTRATION

Spinal Cord Injury

Spinal Cord Injury

61 patients with SCI

follow-up after 6 monthsMean time since diagnosis was 72 monthsNO PATIENT PRESENT MAYOR SIDE EFFECTS62% improved the muscular strength50% improved the spasticity 37% improved the bladder control93% of them referred a better general health status50% had an improved sensibility

Stroke

Denes, A., Coutts, G., Lnrt, N., Cruickshank, S.M., Pelegrin, P., Skinner, J., Rothwell, N., Allan, S.M., Brough, D., 2015. AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc. Natl. Acad. Sci. 201419090. doi:10.1073/pnas.1419090112.Friedrich MA, Martins MP, Araujo MD et al (2012) Intra-arterial infusion of autologous bone-marrow mononuclear cells in patients with moderate to severe middle-cerebral-artery acute ischemic stroke. Cell Transplant 21(Suppl 1):1321Savitz SI, Misra V, Kasam M et al (2011) Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol 70:5969

These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain. (Denes et al. 2015)

(Friedrich et al. 2008)

(Savitz et al. 2008)

Cardiac disease

CARDIAC DISEASE

BEFOREAFTER

CARDIAC DISEASE

One NYHA class overall improvement

CARDIAC DISEASE

Improvement in EF and LVESV

Wound healing, septic fractures, septic wounds, etc.8 months therapy resistant Decubital ulcer at time of stem cell surgery and follow up 9 months p.o.

Regulatory situationThe European Union (EU) recognize that conventional non-clinical pharmacology and toxicological studies may be different for cell-based drugs and has issued the Directive 1394/2007 on Advanced Therapy Medicinal Products (ATMPs) including gene therapy medicinal products, somatic cell therapy products and tissue engineered products(151). Then, the Directive 2004/23/EC states that Tissues and cells used as an autologous graft within the same surgical procedure are exempt from a Cell and Tissue Directive (Article 2 section 2(a) page 4). Further, in the European Union authorities decisions in the Meeting of the Competent Authorities for Tissues and Cells is conclude that Tissues and Cells... when used to the same individual within the same surgery process, in the same operating room, when cells used with the same essential function, should be exempted from the Cell & Tissue Directive 2004/23/EC( section 3.3. page 7).

Regulatory situationIn the Directive 1394/2007 (Recital 14 Page 2), above mentioned, states that This regulation should not derogate from the basic principles laid down in Directive 2004/23/EC, but should supplement them with additional requirements, where appropriate, statement that is repetitive through the document also in recital 22 and Article 2 (page 3 and page 4). The above mentioned means that both directives work in harmony and share definitions and a basic principle of Directive 2004/23/EC is that autologous cells used in the same surgical procedure do not filled the scope of the directive and in consequence cannot be taken into account in the directive 1294/2007 as ATMPs. Not bringing this basic principals forward into 13294/2007 violates the spirit of Recital 14.

Regulatory situationThe placing on the market of medicinal products for human use, meaning the first making available in the return for payment... with a view to distribution and or use in the community market as states in the Directive 93/42/EEC (B)(h) page 7)(154), is determined in the Directive 2001/83/EEC (Article 2- page 16 )(155) a directive that shall apply to medicinal products for human use intended to be placed on the market in member states. According to this directive the autologous point of care transplantation should attach to the place on the market regulation just for the devices and reagents (Sepax 2), together with a CE mark, such as our devices and reagents are. However, the cell output from the device (autologous bone marrow-derived stem cells) are not subject of placed on market regulations. Furthermore, the cell output is also exempt in the EU Blue Guide for manufacturing while is not officially placed on the market (Section 2.3 - page 17). The first step to determined a medical product as an ATMP is to be part of the place on the market regulation.

Regulatory situationThe Human Tissue Authority (HTA), the British regulatory agency, in the position statement HTA-POL-067b regarding our procedure, a document on the regulation of processing and distribution, when carried out as part of a single surgical procedure does not require a HTA license (pages 6 and 7).

Regulatory situationThe Food and Drug Administration (FDA), in The United States of America, in the Code of Federal Regulations 21 CFR 12.71.15(b) You are not required to comply with the requirements of this part if you are an establishment that removes human cells, tissues, and cellular and tissue-based products (HCT/P's) from an individual and implants such HCT/P's into the same individual during the same surgical procedure.( Code of Federal Regulations 21 CFR).

Regulatory situationIn conclusion our treatment does not require special legislation or regulation while it is not an ATMPs.

It could be performed as a regular surgical procedure.

WORLDWIDE CLINICAL TRIALS

4692 studies found for: STEM CELLSThe EU Clinical Trials Register currently displays 24292 clinical trials with a EudraCT protocol, of which 3259 are clinical trials conducted with subjects less than 18 years old. The register also displays information on 10296 older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

Our scientific contributions

Kobinia, Georg, Ruiz-Navarro, Francisco. Aluminiumspiegel im liquor, ergebnisse bei 141 patienten mit neurologischen erkrankungen. Unstoppable Public Health - Denken ber Grenzen hinweg. 18. Wissenschaftliche Tagung der sterreichischen Gesellschaft fr Public Health; 2015 mai; St. Plten. Ruiz-Navarro, Francisco, Kobinia, Georg. Aluminum levels in cerebrospinal fluid of patients with Amyotrophic Lateral Sclerosis are dose-related to worse clinical status and mortality. 51st Congress of the European Societies of Toxicology; 2015; Portugal. Matzner Mi, Shaw C, Morrice J, Kobinia G. Bone Marrow stem cell vitality and count decreases with elevated aluminum levels. ISSCR 2014 Annu Meet Poster Abstr. 2014; Hazem, Khamis, Mohamed, Shoukry, Ruiz-Navarro, Francisco, Kobinia, Georg. Cardiac Point-Of-Care Stem cell Therapy (C-POCST): Preliminary results of a new method. 2nd International Annual Conference of the German Stem Cell Network (GSCN); 2015 Nov 3; Heidelberg, Germany. Matzner, MIchael, Shaw, Chris, Morrice, Jess, Ruiz-Navarro, Francisco, Kobinia, Georg. CD34+ cell counts and their relationship to clinical factors in 281 patients undergoing autologous stem cell transplant. World Stem Cells Regenerative Medicine Congress 2014; 2014; London, UK. Ruiz-Navarro, Francisco, Kobinia, Georg. Neuron Point-Of-Care Stem cell therapy: Intrathecal transplant of autologous bone marrow-derived stem cells in patients with cerebral palsy. Preliminary Results. Tissue science and Regenerative Medicine; 2015 Jul; Rome, Italy. Ruiz-Navarro, Francisco, Kobinia, Georg. Neuron point-of-care stem cell therapy (N-POCST): Transplantation of autologous bone marrow-derived stem cells for traumatic central nervous system disorders, the future of a new method. World Congress on Cell and stem cell research; 2015 Mar; Chicago, USA. Kobinia, Georg. Processing of bone marrow for stem cell infusion. Cell culture and bioprocessing Forum; 2014 Oct; Berlin, Germany. Kobinia G, Ruiz-Navarro F. Statistical relationship between levels of autologous bone marrow-derived CD34+ and clinical status of patients with amyotrophic lateral sclerosis. ISSCR 2015 Annual meeting.; 2015 Jun; Stockholm. Ruiz-Navarro F, Kobinia G. Stem cell therapy for amyotrophic lateral sclerosis follow-up of 84 patients. J Cell Sci Ther. 2014 Jun;

OUR EXPERIENCE

800 PATIENTS

INTERNATIONAL COLLABORATIONS

Bulgaria, Romania, Iran, Kazakhstan, Serbia, Croatia, England, Egypt

Researchers and biotech executives foresee the day when the effects of many catastrophic diseases can be reversed. The damaged brains of Alzheimer's disease patients may be restored. Severed spinal cords may be rejoined. Damaged organs may be rebuilt. Stem cells provide hope that this dream will become a reality.

GEORGE WOLFF, The Biotech Investor's Bible