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WO2010062999A1 - Thérapie cellulaire du diabète - Google Patents

Thérapie cellulaire du diabète Download PDF

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Publication number
WO2010062999A1
WO2010062999A1 PCT/US2009/065999 US2009065999W WO2010062999A1 WO 2010062999 A1 WO2010062999 A1 WO 2010062999A1 US 2009065999 W US2009065999 W US 2009065999W WO 2010062999 A1 WO2010062999 A1 WO 2010062999A1
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WIPO (PCT)
Prior art keywords
bone marrow
cells
patient
catheter
patients
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PCT/US2009/065999
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English (en)
Inventor
Alejandro Mesples
Francesca Vitelli
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Stematix, Inc
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Publication of WO2010062999A1 publication Critical patent/WO2010062999A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2053—IL-8
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0041—Catheters; Hollow probes characterised by the form of the tubing pre-formed, e.g. specially adapted to fit with the anatomy of body channels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0009—Making of catheters or other medical or surgical tubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0054—Catheters; Hollow probes characterised by structural features with regions for increasing flexibility

Definitions

  • This invention relates to the treatment of diabetes using stem cells.
  • Diabetes is a global and growing epidemic. In the United States alone, 23.6 million children and adults (7.8% of the population) have diabetes. Current treatment for Type 1 Diabetes does not provide a cure and is very disruptive to quality of life. It also creates massive costs and expenditures for both the individual and our healthcare systems. In the U.S., the total annual economic cost of diabetes in 2007 was an estimated $174 billion.
  • Other autoimmune disorders including rheumatoid arthritis, Charcot-Marie-Tooth disease, Crohn's disease, Addison's disease, Graves' disease, lupus erythematosus, myasthenia gravis, pernicious anemia, and multiple sclerosis also pose substantial burdens to our health and health care system.
  • Cell therapy describes the process of treating a medical condition by replacing diseased or dysfunctional cells with healthy, functioning ones.
  • a classic example is bone marrow therapy for cancer, whereby the patient is irradiated and the bone marrow repopulated with healthy bone marrow.
  • bone marrow cells In addition to bone marrow cells, a large range of cells can serve in cell therapy including blood cells and mature and immature solid tissue cells.
  • Stem cell therapy is a more recent type of cell therapy specifically using stem cells to treat a medical condition.
  • Stem cells are primitive, unspecialized cells that have the capacity to self-renew and to differentiate into mature, specialized cells.
  • human stem cell preparations are either embryonic stem cells — derived from embryos — or adult stem cells — derived from various adult tissues.
  • Human embryonic stem cells were first derived from human blastocysts in 1998. They are totipotent, meaning they can become any of the more than 200 known differentiated cell types of the human body. Embryonic stem cells are found in the embryo until about five days after fertilization.
  • Adult stem cells also known as somatic stem cells — exist in many tissues of the human body (in vivo) at any age after birth (newborn to adult), and are the body's own mechanism for tissue turnover and regeneration to repair specific damage or normal 'wear and tear.
  • Adult stem cells in the human body are quite rare compared to the somatic cells and often are difficult to identify, isolate and purify. They are most commonly identified by protein markers on their surface, such as CD34 on hematopoietic stem cells (HSCs), one category of adult stem cells.
  • HSCs hematopoietic stem cells
  • Induced pluripotent stem cells are pluripotent stem cells derived from somatic cells by treatment with specific proteins, nucleic acids, and/or viruses.
  • HSC pluripotent hematopoietic stem cells
  • MSC multipotent mesenchymal stromal cells
  • HSCs regenerate all cell types in the blood and the immune system
  • MSCs can regenerate many tissues including bone, fat, cartilage and muscle.
  • the bone marrow contains both HSCs and MSCs.
  • adult stem cells have been detected in many tissues including: bone marrow, blood (umbilical cord and peripheral blood), brain, dental pulp, cornea, liver, skin, adipose tissue, and heart.
  • Non-hematopoietic bone marrow stromal cells within adult bone marrow, including reticular cells, smooth muscle cells, adipocytes and osteoblasts, provide the local environmental cues necessary to support the survival, proliferation and differentiation of hematopoietic stem cells (HSC).
  • HSC hematopoietic stem cells
  • Alexander Friedenstein and associates were the first to demonstrate in the '70s that bone marrow explants placed in the kidney of recipient mice could form bone-like tissue that was capable of self-renewal and self- maintenance and could support the formation of blood cells.
  • CFU-Fs colony- forming unit fibroblasts
  • stromal populations are derived from multipotential bone marrow stromal cells (BMSC) or subsets that are also referred to as bone marrow stromal stem cells (BMSSC), mesenchymal stem cells/marrow stromal cells (MSC), marrow-isolated adult multipotent inducible cells (MIAMI), multipotent adult progenitor cells (MAPC) and mesenchymal adult stem cells (MASCS).
  • BMSC bone marrow stromal stem cells
  • MIAMI mesenchymal stem cells/marrow stromal cells
  • MIAMI marrow-isolated adult multipotent inducible cells
  • MMC multipotent adult progenitor cells
  • MASCS mesenchymal adult stem cells
  • CFU-F colony forming unit fibroblast
  • MHC class I may activate T cells, but, with the absence of costimulatory molecules, a secondary signal would not engage, leaving the T cells anergic.
  • MSCs have also described MSCs as having immunosuppressive properties — specifically that MSCs can modulate many T-cell functions including cell activation. This suppression appears to be independent of MHC matching between the MSCs and the T cells. Some reports have demonstrated that direct cell-cell contact is required for suppression, whereas others have shown that the suppressor activity depends on a soluble factor. It has also been shown that MSCs have immunomodulatory properties impairing maturation and function of dendritic cells and that human MSCs inhibit in vitro human B-cell proliferation, differentiation, and chemotaxis.
  • MSCs show great promise as a biological therapeutic for a diverse range of unmet medical needs. The reasons for this are many and include: ease of isolation and expansion in culture, multipotency, paracrine effects, immunomodulatory properties, migratory behavior and favorable ethical considerations. In recent years it has also come to light that MSC plasticity extends beyond the conventional bone, adipose, cartilage, and other skeletal structures, and has expanded to the differentiation of liver, kidney, muscle, skin, neural, and cardiac cell lineages. Thus, their use is expected to further increase as a variety of disease conditions can be treated with these cells.
  • the invention generally relates to method of treating a patient with whole bone marrow or marrow stem cells, wherein the cells are harvested following low dose mobilization of MSCs, as defined below.
  • Such cells can be used to treat any disease currently treated with bone marrow or marrow derived stem cells.
  • the cells can be used as is, or can be further purified or amplified before use pursuant to existing treatment protocols, and if needed the treatment can be combined with other treatments such as immunosupression and the like.
  • the method can be used to treat any disease that is responsive to bone marrow therapy, including those described in Table 1 and can be combined with most, if not all of the existing methodologies, including those of Table 2.
  • “Low dose mobilization” is defined herein as that low dosage over a period of 3-9 days of a mobilization factor, sufficient to raise circulating MSC level, as assessed by CD34+ cell counting, to 0.02-0.05%.
  • target CD34+ levels are 0.03%, corresponding to a CD34+ count in the bone marrow of about 0.12X10 8 cells/kg body weight. If after 5 days the CD34+ levels do not reach 0.03%, the patient will receive 2 additional days of mobilization, and CD34+ cells will be subsequently re-measured. If the target of 0.03% has been reached, the patient continues with the procedure, otherwise the patient is excluded from the protocol. Failure to achieve mobilization in 7-9 days indicates that the dose is too low and should be increased.
  • CD34+ cells found in the peripheral circulation are measured by flow cytometry of cells labelled with fluorescently labeled anti-CD34 antibodies, and low dose mobilization continues until the requisite level is achieved, as described above.
  • mobilization factor means a pharmaceutically acceptable agent that stimulates the physiological increase of stem and progenitor cells in the bone marrow, and includes among others G-CSF, IL-8, Mobozil, POL6326, Flt3L, PTH and cyclophosphamide and active variants and combinations thereof and other treatments having similar effects.
  • mobilization is achieved by a dosage of
  • mobilization is achieved as once-daily injections of 5 ⁇ g/kg IV Filgrastim.
  • the invention relates to method of treating type I diabetes patients with untreated bone marrow cells, wherein the patient is not pretreated by immunoablation or immunosupression, and the therapeutic cells are obtained directly from the bone marrow (without intervening purification and/or amplification) following low dose mobilization of MSCs.
  • untreated bone marrow or “whole bone marrow” means bone marrow cells that are not purified for one or more cell types, but rather comprise the normal mobilized marrow cell population, and are not amplified after harvesting in any way. Specifically included within the scope of these phrases are minor treatments such as filtration or centrifugation to remove bone fragments and blood clots, and the addition of other agents such as clotting agents or antibiotics and other drugs.
  • the phrase "the patient is not immunoablated or immunosuppressed” means that the patient is not or has not been recently treated with radiation or chemical agents to suppress or destroy the bone marrow or immune system. Specifically excluded from the term is the endogenous levels of immunosupression that may arise from lifestyle choices or disease, as well as any immunosupression that may arise from subsequent transplant of stem cells, bone marrow, or MSCs.
  • patient includes human and animal patients.
  • autologous cells are preferably transplanted, but in others allogeneic transplants are preferred or a mixture thereof.
  • cell are administered at the same time as a factor to enhance targeting of the stem and progenitor cells to the organ and increasing organ function.
  • Targeting factors include, without limitation, DPPIV, TNFa, VEGF, IGF, EGF, gastrin, fucosyl transferase, and aldehyde dehydrogenase inhibitors such as DEAB, as well as other treatments achieving similar effects.
  • the transplanted cells are a mixture of autologous bone marrow stromal cells and allogeneic mesenchymal stem and progenitor cells derived from donor stromal tissues including the umbilical cord matrix, Wharton's jelly, perivascular cells surrounding the umbilical cord vessels, placental cells including amniotic, chorionic, epithelial and endothelial progenitors, cord blood derived mesenchymal progenitors including unrestricted somatic stem cells and endothelial progenitors, menses-derived cells with pluri-lineage potential and generally cells that are positive for one or more of CDl 05, CD90, CD73, CD44, Stro-1, VCAM but negative for CD45, CD34, HLA-DR, and bone marrow stromal cells derived from bone marrow puncture.
  • donor stromal tissues including the umbilical cord matrix, Wharton's jelly, perivascular cells surrounding the umbilical cord vessels, placental cells including amn
  • the allogeneic cells are derived from a donor of fetal islet cells combined with autologous bone marrow derived cells, hi a more preferred embodiment, the cells are a mixture in the range of 3:1-2:1 autologous to allogeneic cells ranging from 1-10 6 cells/kg. In an even more preferred embodiment, the cells comprise morphologically small, rapidly self-renewing cells from the bone marrow stroma.
  • the cells are autologous stem cells induced toward the formation of islets, mixed with alginate or other polymer or matrix, or with other donor cells, or targeting agents, or antibodies.
  • the invention also relates to a method of delivering cells for cell therapies, wherein the cells are injected into an artery at or near the target location, whereby the proximity to the target site facilitates mobilization of the cells into the target tissue, and the delivery method causes little or no trauma to that tissue.
  • the bone marrow cells are injected directly into a pancreatic artery, and most preferably, the cells are placed into one or both of the superior mesenteric or celiac trunk artery.
  • FIG. 1 Another embodiment of invention is a novel catheter that can be used to deliver cells or other therapeutics directly to pancreatic internal arteries with less risk of damage to the artery.
  • Figure 1 depicts a modified catheter designed to release the cell sample into the pancreatic artery.
  • the catheter generally comprises a long hollow tube, sized to fit within the pancreatic artery, wherein the tip of the catheter has three sections, each placed at an angle to the other.
  • the first segment, proximal to the handle, contains a length between 0.1-1.5 cm and a slope comprising between 10-40 degrees from the vertical axis
  • the second contains a length between 1-6 cm and a curvature such that the endpoint is on a line between 40-80 degrees from the vertical axis
  • a third distal-most segment comprising a length between 0.5-3 cm, such that the endpoint of the catheter falls on a line with slope of 120-160 degrees from the vertical axis.
  • the catheter tip has a first portion A closest to the handle that is about 1-2 cm long (preferably 1.45 cm) and is at about 20-30° to the handle (preferably 25-26°), a second portion B that is about 3-4 cm long and at about 65-75° to the handle (preferably at 72°), and a distal portion C that is about 0.5-1.5 cm long (preferably 1 cm), and at an angle of 130-145° (preferably at 142°).
  • the catheter tip has a constant diameter of at 1.2-1.6 mm, preferably 1.4 mm, and all segments are within 0-0.5 cm of co- planarity.
  • the catheter can be made of any suitable non-toxic, biocompatible material.
  • suitable non-toxic, biocompatible material for example, polypropylene, polyethylene, polyether block amides, urethane elastomer, polytetrafiuoroethylene, and the like can be used.
  • the catheter can also be made on metal, ceramic or glass or other material and coated with a biocompatible polymer, such as teflon, silicone and the like.
  • the catheter has multiple sections with graded stiffness and the tip is softer than other parts of the catheter.
  • the catheter can also have a hydrophilic coating, preferably a lubricious hydrophilic coating.
  • the catheter can also have a guide wire for facilitating introduction of a flexible catheter into the body and/or a radio-opaque element for improved visualization during the procedure.
  • the catheter has smooth transitions, made by extrusion, and in another embodiment, the catheter is re-shapeable to meet the required architecture.
  • the durability and luminal changes of the catheter tip are maintained by proper selection of starting catheter materials and by minimizing surface changes and luminal irregularity so that the catheter may be re-sterilized and re-used many times.
  • the catheter has a internal root-mean-square (rms) roughness below about 29 ⁇ A, and preferably below about 12 ⁇ A.
  • the cells are administered using a catheter with internal diameter of about 700 ⁇ m, and preferably below about 500 ⁇ m.
  • FIG. 1 presents a catheter used for administration of cells and/or fluids to the pancreatic circulation.
  • FIG. 2 presents data on reduction of insulin usage after treatment.
  • FIG. 3 presents data on AlC levels after treatment. This chart shows glycosylated Hb AlC levels. Three groups are presented with responder, partial responders and non responders and the patients in the same order as previously. For patients 12, 1, 2, and 3, the AlC values reduced rapidly and remained in the "normal" range during the following years. Some Responders actually saw an increase in AIc levels (patient 5), while others in the non-responder group showed a significant decrease in AIc, in some cases well within range for normal, suggesting that even if they did not get off insulin entirely, they were able to better manage their diabetes.
  • FIG. 4 presents data on peptide C levels after treatment.
  • the left-most bars per patient are the values of C peptide before implantation. Note that all were below 0.05.
  • Patients in the responder group had level near normal (gray shading) from 6 months post treatment up to 3 years for 6 patients out of 9.
  • the level of C peptide rose also significantly in the partial responders.
  • Patient 7 did not have any change in insulin usage, but presented a significant increase from 6 months to 3 years indicating some effect of the therapy.
  • C peptide levels are a good marker of clinical outcome to the implantation, and this is not surprising as it is associated with regained organ function.
  • FIG. 5 presents data on overall results after treatment. 45% of patients were off insulin for at least one time point. 70% of patients had their C peptide levels in the "normal" range for at least 6 months indication of recovery of partial organ function, and finally, 45% of the patient had a significant reduction in their AlC level after treatment indicating better clinical management of their diabetes.
  • Table 1 Diseases treated with bone marrow or stem cell transplants
  • Leukemias such as Acute lymphoblastic leukemia, Acute myelogenous leukemia, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, accelerated phase or blast crisis
  • Lymphomas such as Hodgkin's disease, Non-Hodgkin's lymphoma
  • Myelomas including Multiple myeloma including Multiple myeloma (Kahler's disease)
  • Solid tumors such as Neuroblastoma, Desmoplastic small round cell tumor, Ewing's sarcoma, Choriocarcinoma
  • Phagocyte disorders such as Myelodysplasia
  • Anemias such as Paroxysmal nocturnal hemoglobinuria and Aplastic anemia (e.g., Acquired pure red cell aplasia)
  • Myeloproliferative disorders such as Polycythemia vera; Essential thrombocytosis; Myelofibrosis
  • Amyloidoses such as Amyloid light chain amyloidosis
  • Lipidoses disorders of lipid storage
  • Neuronal ceroid lipofuscinoses Infantile neuronal ceroid lipofuscinosis (inc. Santavuori disease); Jansky-Bielschowsky disease (late infantile neuronal ceroid lipofuscinosis) and Sphingolipidoses such as Niemann-Pick disease; Gaucher disease
  • Leukodystrophies such as Adrenoleukodystrophy; Metachromatic leukodystrophy; Krabbe disease (globoid cell leukodystrophy)
  • Mucopolysaccharidoses such as Hurler syndrome; Scheie syndrome; Hurler-Scheie syndrome; Hunter syndrome; Sanfilippo syndrome; Morquio syndrome; Maroteaux-Lamy syndrome and Sly syndrome
  • Glycoproteinoses such as Mucolipidosis II; Fucosidosis; Aspartylglucosaminuria; Alpha- mannosidosis
  • T-cell deficiencies such as Ataxia telangiectasia, DiGeorge syndrome
  • Combined T- and B-cell deficiencies such as Severe combined immunodeficiency (SCID), all types
  • Phagocyte disorders such as Kostmann syndrome; Shwachman-Diamond syndrome
  • Immune dysregulation diseases such as Griscelli syndrome, type II
  • Hematologic diseases including Hemoglobinopathies; Sickle cell disease; ⁇ thalassemia major (Copley's anemia)
  • Anemias such as Aplastic anemia; Diamond-Blackfan anemia; Fanconi anemia
  • Cytopenias such as Amegakaryocytic thrombocytopenia
  • Hemophagocytic syndromes such as Hemophagocytic lymphohistiocytosis (HLH)
  • Negative anti-GAD glutamic acid decarboxylase
  • Target organs not affected renal failure with creatinine clearance below 50 ml/min, diabetic retinopathy at advanced stages, advanced arteriopathy in the lower limbs, antecedents of acute coronary syndrome, myocardial infarction or stroke, and vascular surgery).
  • Basal C peptide level was measured in peripheral blood . Levels were measured again at 6 and 12 months using an electrochemiluminiscence technique. The following results were regarded normal values in serum and plasma: 1.1-4.4 ng/ml, and 0.05 ng/mL analytical sensitivity of serum.
  • ICAs were measured prior to implantation and at 12 months follow- up time through quantitative indirect immunofluorescence (reference value: negative).
  • Anti-GAD antibodies were measured by radioligand binding (reference: ⁇ 1 U/ml: negative value, and > 1.01 U/ml: positive value).
  • Analyzed variables were age, sex, exogenous insulin daily requirement, fasting and post-prandial glycaemia, glycated haemoglobin rate, C peptide, anti-pancreatic islet antibodies and anti-GAD follow-up levels and abdominal imaging. Variables were analysed prospectively, and non-randomized.
  • Cytometric analysis of the CD34+ cells was performed according to the standardized guidelines set forth in the ISHAGE (International Society of Hematotherapy and Graft Engineering) 23 protocol (Reference; Current status of CD34+ cell analysis by flow cytometry: The ISHAGE guidelines Clinical Immunology Newsletter, Volume 17, Issues 2-3, February-March 1997, Pages 21-29 by Ian Chin-Yee, Michael Keeney, Lori Anderson, Rakesh Nayar, D. Robert Sutherland). Specifically, cells were double-labeled using CD34+ and CD45 antibodies. CD45 is a pan-leukocyte marker used to increase specificity of CD34+ measures by flow cytometry.
  • bone marrow from the posterior iliac crest was extracted.
  • a trocar puncture was made, 60 to 80 ml of bone marrow were aspirated and mixed with sodic heparin (5.000 UI/20ml).
  • Total bone marrow was morphologically evaluated with viability determinations (>75%), and filtered to ensure absence of blood clots, bone fragments and to ensure sterility. No cultures or in vitro enrichment procedures were performed.
  • Implantation Procedures A puncture was made in the femoral artery. A guide catheter was introduced through a 5F arterial introducer, into the superior mesenteric or celiac trunk artery under radioscopic and digital angiography. The lower pancreatic artery was identified and a perfusion micro-catheter was selectively placed. The collected and filtered bone marrow cells were injected into the artery and the procedure was completed.
  • Selective catheterization of a target vessel is defined by successful placement of guide catheter and successful progression of micro catheter along the lower pancreatic artery, without any complications.
  • Angiographic complications are defined as events such as embolism, thrombosis, vessel dissections or spasms, or complication of the arterial puncture process such as embolism, thrombosis, dissections, haematomas requiring surgery or blood transfusions or transfusion of blood elements. While angiographic visualization of pancreatic blush is desirable, the lack of pancreatic blush is not to be considered a complication due to angiography.
  • 12-month Results 14 patients: None of the treated patients changed body weight by over 10% of weight prior to implantation. Six patients attained total suppression of daily insulin dose, normal basal C peptide values, fasting and post prandial glycaemia and glycated haemoglobin levels. No blood count and renal function laboratory test changes were observed.
  • Glycaemia Level Patients took daily fasting and postprandial glycaemia self-tests at least twice during the post-implantation period. It was observed that 18 out of the 22 patients had symptomatic hypoglycaemic episodes not related to other causes (42 mg/dl average, 20 to 58 mg/dl range), at different times during the day and at least for three consecutive days before decreasing their insulin administration. Such hypoglycaemic episodes were registered as of the first month of follow-up and up to a year of follow-up and were more frequent between the fourth and eighth month after stem cell transplantation. It was observed that hypoglycaemic episodes were always symptomatic, not serious. It was also observed that as of the first month of follow-up, hyperglycaemic episodes (glycaemia above 200 mg/dl any time during the day) were infrequent and it led patients to stop using fast-acting insulin.
  • hyperglycaemic episodes glycaemia above 200 mg/dl any time during the day
  • Glycated Haemoglobin follows-up: At one follow-up year, patients who had managed to suppress exogenous insulin administration and reach normal basal and stimulated C peptide levels, showed a decrease in glycated haemoglobin value until it became normal. Patients who had not managed to suppress exogenous insulin administration or reach normal C peptide levels, showed glycated haemoglobin levels similar to those obtained prior to implantation with a 1% variation in some cases.
  • C Peptide Level After the observed that patients who had attained total suppression of insulin administration reached normal levels of basal and stimulated C peptide. Patients who had decreased their daily insulin administration dose by over 66% showed a C-peptide level increase at least three times higher than that obtained prior to implantation, although they had not reached normal values. No significant changes in C peptide level were observed in patients who had decreased their daily insulin administration dose by 50%, or in patients that showed no clinical changes.
  • the efficacy of the therapy regime and the function of the implanted bone marrow cells may be attributable to various specific functions of the cells. Specifically, mobilizing marrow stem cells to peripheral blood may contribute to systemic immune suppression. Additionally, local delivery of bone marrow has been shown to encourage local neo-vascularization, which may serve to further aliment the pancreatic tissue. Based on increased C-peptide levels observed in 70% of patients, some organ function is reached, which may be attributable to transdifferentiation events and/or local action of cytokines and chemokines signaling to local resident progentiors and other cells able to respond to paracrine factors released by the cells.
  • a single patient never produced significant changes post- implant. No adverse events were observed.
  • Evolution of blood glucose The patients underwent daily blood glucose self-analysis and post-prandial fasting at least twice. It was noted that patients had episodes of symptomatic hypoglycemia, unrelated to other causes (42 mg / dl average range of 20 to 58 mg / dl), at different times of day and at least three consecutive days before of lower doses of insulin. Episodes of hypoglycemia were found from the first month, and until follow-up, occurring more frequently between the fourth and eighth month of evolution. It was noted that the hypoglycemic episodes were always symptomatic, and never serious. It was also observed from the month of evolution that episodes of hyperglycemia (blood glucose above 200 mg / dL at any time of day) were rare prompting patients to abandon the use of rapid-acting insulin.
  • Patients suffering from Type 1 diabetes are subjected to catheterization via a puncture made in the femoral artery.
  • Guide catheter measuring 5F and side holed sheath introducers are placed in the superior mesenteric or celiac trunk artery under radioscopic and digital angiography.
  • the lower pancreatic artery is identified and a perfusion micro-catheter is selectively placed and cell-free buffer solution injected in the artery.
  • the implant procedure is completed.
  • Filgrastim granulocyte colony stimulating factor G-CSF
  • G-CSF granulocyte colony stimulating factor
  • ISHAGE 23 is the protocol used to quantize CD34+ cells using anti-CD45-FITC, anti-CD34-PE and isoty ⁇ e-PE control monoclonal antibodies.
  • Bone marrow from the posterior iliac crest is extracted.
  • a trocar puncture is made, 60 to 80 ml of bone marrow is aspirated and mixed with sodic heparin (5.000 UI/20ml).
  • Filtered bone marrow is morphologically evaluated for feasibility determinations, absence of blood clots, bone residue and bacteria. No cultures or in vitro enrichment procedures are performed.
  • the bone marrow is administered within the heart (intramyocardial) and coronary artery (intracoronary) tissues of heart disease patients utilizing the investigational MYOSTAR Injection Catheter, researchers administer bone marrow-derived stem cells into patients' left heart ventricle, relying on the NOGA System to aid in accurately identifying the target injection site.
  • Filgrastim granulocyte colony stimulating factor G-CSF
  • G-CSF granulocyte colony stimulating factor
  • ISHAGE 23 is the protocol used to quantize CD34+ cells using anti-CD45-FITC, anti-CD34-PE and isotype-PE control monoclonal antibodies.
  • Bone marrow from the posterior iliac crest is extracted.
  • a trocar puncture is made, 60 to 80 ml of bone marrow are aspirated and mixed with sodic heparin (5.000 UI/20ml).
  • Filtered bone marrow is morphologically evaluated for feasibility determinations, absence of blood clots, bone residue and bacteria. No cultures or in vitro enrichment procedures are performed.
  • the bone marrow cells are mixed with an equal number of HUCPVC cells and administered intravenously to patients with Type I diabetes.
  • Filgrastim granulocyte colony stimulating factor G-CSF
  • G-CSF granulocyte colony stimulating factor
  • ISHAGE 23 is the protocol used to quantize CD34+ cells using anti-CD45-FITC, anti-CD34-PE and isotype-PE control monoclonal antibodies.
  • Bone marrow from the posterior iliac crest is extracted. A trocar puncture is made, 60 to 80 ml of bone marrow are aspirated and mixed with sodic heparin (5.000 UI/20ml). Filtered bone marrow is morphologically evaluated for feasibility determinations, absence of blood clots, bone residue and bacteria. No cultures or in vitro enrichment procedures are performed.
  • the bone marrow is administered along with an affinity targeting agent (a bispecific antibody) into the pancreatic circulation of patients with type I diabetes.
  • the above-mentioned catheter has a very curved distal segment, due to the anatomical position of where the left mammary artery originates, therefore we tried to adjust to widen the angle of curvature. This was successfully achieved but the catheter was short and was not selective. For this reason, we further modified the first angle in the body of the catheter that was formerly straight. With this modification, the catheter was then sufficiently long to successfully perform selective catheterization. Furthermore, since the distal segment was short, it was possible to safely maneuver the catheter within the mesenteric trunk to guide the catheter into the hepatic circulation, and place within it the cerebral microcatheter.
  • the catheter generally comprises a long hollow tube sized to fit within an artery.
  • the tip of the catheter that has three sections, each placed at an angle to the other.
  • the catheter tip has a first portion A closest to the handle that is about 1-2 cm long (preferably 1.45 cm) and is at about 20-30° to the handle (preferably 25- 26°), a second portion B that is about 3-4 cm long and at about 65-75° to the handle (preferably at 70-72°), and a distal portion C that is about 0.5-1.5 cm long (preferably 1 cm), and at an angle of 120-160° (preferably at about 140-142°).
  • the segment may be straight or more or less curved (not shown), so long as the distal most end of the segment lies at the degree from vertical required.

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Abstract

L’invention concerne des procédés de traitement de patients à l’aide de moelle osseuse mobilisée à faible dose. Le procédé a prouvé son efficacité dans le traitement du diabète de type 1, même lorsque les cellules de moelle ne sont pas davantage purifiées ni amplifiées, et même lorsque le patient ne reçoit ni traitement immunosuppresseur, ni traitement immunoablatif. L’invention concerne également de nouveaux dispositifs et procédés d'administration.
PCT/US2009/065999 2008-11-28 2009-11-25 Thérapie cellulaire du diabète WO2010062999A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US20043808P 2008-11-28 2008-11-28
US61/200,438 2008-11-28

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WO2010062999A1 true WO2010062999A1 (fr) 2010-06-03

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030235909A1 (en) * 2002-04-12 2003-12-25 Hariri Robert J. Modulation of stem and progenitor cell differentiation, assays, and uses thereof
US20060003312A1 (en) * 2002-11-01 2006-01-05 Stanford University Circulating stem cells and uses related thereto
US20070020757A1 (en) * 2005-05-24 2007-01-25 Whitehead Institute For Biomedical Research Methods for expansion and analysis of cultured hematopoietic stem cells
US20070274970A1 (en) * 2003-12-19 2007-11-29 Myrtle Gordon Stem Cells

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030235909A1 (en) * 2002-04-12 2003-12-25 Hariri Robert J. Modulation of stem and progenitor cell differentiation, assays, and uses thereof
US20060003312A1 (en) * 2002-11-01 2006-01-05 Stanford University Circulating stem cells and uses related thereto
US20070274970A1 (en) * 2003-12-19 2007-11-29 Myrtle Gordon Stem Cells
US20070020757A1 (en) * 2005-05-24 2007-01-25 Whitehead Institute For Biomedical Research Methods for expansion and analysis of cultured hematopoietic stem cells

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