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Disease Teams align with CIRMs mission and clinical strategic objective
CIRMs mission is to advance stem cell research for the discovery and development of cures, therapies, diagnostics and research technologies to relieve human suffering from chronic disease and injury. Key strategy to progress stem cell science into clinical trials, CIRM funded 14 multidisciplinary Disease Teams in 2010
Initiate the development studies, potentially leading to successful filing of an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) for these stem cell based therapies to enter human clinical trials over the next 4 years
Preclinical Research
Preclinical Dev.
Fundamental Biology
File IND
Targeted Clinical Development Tools & Technologies Disease Team Research II Transplantation Immunology
CIRMs Disease Teams, addressing major unmet clinical needs, are moving towards the clinic
Basic Basic Research Research Discovery Discovery Research Research Preclinical Preclinical Research Research
DEVELOPMENT CANDIDATE
Early
FILE IND
Diabetes (1) Neurological Disorders (2) Eye Disease (1) Cardiac Disease (1) HIV/AIDS (2) Cancer (5) Blood Disorders (1) Skin Disease (1)
Milestones and expert advice, to better position the Disease Teams (DTs) for success
After ICOC approval and before funding, CIRM and DTs agreed on Go/No Go and progress milestones and criteria to inform decisions; budget to support proposed activities Complementing quarterly and annual reporting with CIRM, DTs met with CIRM and panels of clinical development advisors at 12 to 18 months of their progress; will continue to meet on annual basis Convening of clinical development advisors to provide external input into milestone process was approved in concept plan for DT solicitation, identified in the DT RFA, and subsequently communicated to all of the DTs
To prevent even the appearance of conflict of interest (COI), CIRM applied GWG COI rules. Clinical development advisors who had a financial, professional or personal COI with respect to one of the awards were disqualified from participating in the panels deliberations
Provided advice and recommendations on project strategy, progress in meeting goals and go/no-go decision points, and approaches to meeting challenges in their product development plans Recommendations provided to Senior Vice President, Research and Development, and CIRM considered this advice in subsequent internal deliberations about the merit of continued support, and under the guidance of the President, made final decisions and followed-up with the DTs on these issues
Advisors
Deborah Armstrong, MD Johns Hopkins Kimmel Cancer Ctr Jonathan Auerbach, PhD GlobalStem Merry Lee Bain, MS Partner, NDA Partners, LLC Nessan Bermingham, PhD BioEquity Capital, LLC Lauren Black, PhD Charles River Laboratories Rajesh Chopra, PhD, BSc; MBBS;FRCP, FRCPath Celgene Corporation Alan F. Cruess, MD, FRCSC Dalhousie University David T. Curiel, MD, PhD Wash Univ School of Medicine Howard Fine, MD Natl Cancer Inst; Natl Inst Neurol Disorders and Stroke Joyce Frey-Vasconcells Pharmanet Derek Hei, PhD Univ of Wisconsin Anthony Hollander, PhD Univ of Bristol Daniel Hoth, MD Hoth Consulting, Inc Judith Karp, MD Johns Hopkins Kimmel Cancer Ctr Robert Langer, ScD Massachusetts Inst. of Technology Edith P. Mitchell, MD, FACP Kimmel Cancer Ctr at Jefferson
Advisors
Bruce Montgomery, MD CEO Cardeas Pharma Jon Odorico, MD Univ of Wisconsin Raymond Roos, MD Univ of Chicago Michel Sadelain, MD, PhD Memorial Sloan Kettering Cancer Center David Savello, PhD XenoPort, Inc Sean Savitz, MD Univ of Texas Ed Stanley, PhD Monash University Eckhard Thiel, MD Univ Berlin Jeffrey Touchman, PhD Arizona State University Darin Weber, PhD Mesoblast James Wilson, MD, PhD Univ of Pennsylvania Wolfram Zimmermann, MD University Medical Center Gottingen
11
Canada
Karen Dewar, PhD Genome Canada Stephane Pion, MD, PhD CIHR Inst of Cancer Research
Key Accomplishments
Select final therapeutic candidate, develop under good manufacturing practices for the clinic Investigated optimal route, dose of NSC to achieve max % of tumor coverage will inject intracranial; also develop intravenous approach 1000 fold more toxic to brain tumor cells than chemotherapy alone Developed novel iron nanoparticle track stem cells, non-invasive imaging 1 publication, two under review, 11 presentations Founded company, TheraBiologics
Status
Complete preclinical POC efficacy fall/2012, and pre-IND discussion with FDA; no financial or timeline impact to project at this time
Key Accomplishments
Stem cells did not reach brain tumors by intravenous route NSCs and MSCs delivered directly to tumors similar dispersion in tumor Unmodified NSCs had insufficient proliferative capacity for production as therapeutic stem cells In vitro studies showed superior anti-tumor activity when stem cells modified with cytosine deaminase in presence of pro-drug 5FC, compared to TRAIL; in vitro anti-tumor activity of CD + UPRT more rapidly produces toxic metabolites than CD alone 2 publications, developed 2 methods for detecting human cells and xenograft preclinical model for use in therapeutic testing
Key Accomplishments
Shown efficacy with anti-ROR1 monoclonal antibody blocking Wnt5 signaling in CLL stem cells, and with small molecule inhibiting JAK2 kinase in AML in rigorous serial transplant models in preclinical models using patient leukemia cells conducting extensive genomics studies to dev leukemia stem cell biomarker signature of response/resistance for potential utility in individualizing therapies and improving response
Status
CIRM recommended team focus their work on two candidates and two diseases (anti-ROR1 in CLLand JAK2 inhibitors in AML); budgets and timelines being assessed and realigned accordingly
Key Accomplishments
Design ultra-thin matrix ,sufficient mechanical strength for culturing and surgical handling; permeability characteristics mimic membrane back of eye (Bruchs membrane), allows passage of proteins, prevents migration of stem cells 7 patent filings covers the matrix, placement of cells on matrix, methods to produce RPE, method to track cells after implantation and specialized instrumentation for surgical delivery of the implant POC after implantation in preclinical model, showed successful interdigitation of transplanted RPE/matrix with host photoreceptors, with morphological and functional rescue of photoreceptors, rescue of vision Spin-off company Regenerative Patch Technologies
Key Accomplishments
First lead candidate molecule has shown efficacy in preclinical models using human tumors and specifically targeting CSCs, and is moving into IND-enabling studies. Team is working on a second molecule targeting a different novel pathway in CSCs.
Key Accomplishments
Humanized and evaluated a number of candidate anti-CD47 antibodies aimed at CSC in acute myelogenous leukemia(AML) Filed patent covering sequence, uses for their lead therapeutic candidate POC efficacy, eradicated leukemia in tumor-bearing xenograft model of primary leukemic cells from patients with AML Conducting preclinical dose exploration and pilot safety studies MRC funded UK component collecting/analyzing samples from patients enrolled in AML trials to evaluate diagnostic and prognostic value of CD47 and other markers of interest re: drivers of leukemia relapse
Key Accomplishments
Generated cells from different sources of hESCs and are in the process of identifying cell lines with best characteristics of minimal toxicity and efficient production of final cell type POC demonstrating hESC-derived neural stem cells can protect motor neuron viability in preclinical model
Status
On track for selecting a single cell line in mid- 2012; timelines and financials unchanged
Key Accomplishments
Discovered that allogeneic cells appear to be as effective as autologous cells in improving cardiac function in preclinical model, and immune consequences of allogeneic appear to be neglible, and with CIRM support, extended that finding to another preclinical model Allogeneic cells can be obtained in large numbers from donor heart, greatly facilitating scale up and manufacture, enabling highly standardized off the shelf product; CIRM approved switch towards an allogeneic product Selected CSps as therapeutic candiaate and will deliver them by direct injection in to the heart using a special magnetically-guided catheter
Status
IND filing for allogeneic product anticipated in mid-2012; no change in timeline or financials.
Key Accomplishments
Identified unique anti-HIV small RNAs to prevent HIV infection through preventing HIV entry into cells by targeting CCR5 as well as HIV replication through inhibiting different steps of HIV replication cycle. Ongoing studies demonstrate HIV inhibition both in vitro as well as in vivo preclinical model.
Status
No impact on timelines and financials at this time
Key Accomplishments
Selected the single therapeutic candidate with disease modifying activity demonstrated in vitro and in vivo preclinical model, has had their pre-IND meeting with the FDA, and are planning preclinical toxicology studies Presented results of ongoing studies at the American Society of Hematology annual meeting in San Diego in December 2011
Status
If team is able to demonstrate feasibility of obtaining sufficient numbers of CD34+ cells by dual bone marrow harvest then there will be no impact on timelines and financials. The team has already done preclinical POC studies with bone marrow derived CD34+ cells. Other activities will continue as planned.
Key Accomplishments
Team has successfully generated iPSC lines from several patients with the recessive form of DEB
Status
Key Accomplishments
Prototypes tested in preclinical model; in preclinical POC studies, this celldevice combination cured drug-induced diabetes ViaCyte established cell mfr, device mfr proceeding at a scale, level of quality to enable preclinical, clinical testing of the combo product; specifically:
made, qualified cGMP master cell bank that met defined criteria; made cGMP working cell bank; finalized progenitor cell manufacturing process, determined final device configuration for clin testing; device manufacturing facility was designed and built; established preclinical models in collaboration with world-renowned immunologists and testing ability of device to protect cells from allo- and auto-immunity; preparing for pivotal IND enabling studies; developing clinical plan for FIH testing
Two invention disclosures Status received suppl funding from JDRF; in discussion with potential partner;
CIRM needs to consider providing bridging funds to support activities needed to support IND filing within the 4 year period of award
Key Accomplishments
Utilizing research bank of candidate cells, functional recovery demonstrated in 3 preclinical models of stroke in 3 independent labs Continues to establish cell mfr and testing processes to enable preclinical and clinical testing; produced 2 qualification lots that can be elected as master cell bank and working cell bank, based on extensive characterization, func and safety testing Conducted pre-pre-IND meeting with FDA Pursuing less complex mfr process (without hydrogel) in order to bring candidate to IND and FIH testing expeditiously (exploring hydrogel as part of CIRM tools and technology award to optimize technology)
Status
no impact to original timelines and financials at this time
Key Accomplishments
Optimizing methods for adenoviral vector mediated transduction of HSCs and CCR5 disruption; optimized methods for expression of ZFN in HSCs to target CCR5 Dev preclinical model to test stem cell therapy for HIV
Used ZFN to alter CCR5 gene in HSCs, and demonstrated these cells can be transplanted into preclinical model. CCR5 gene encodes cell surf receptor used by HIV to enter cells. When altered HSCs given to preclinical model that lacked effective immune system, cells colonized in bone marrow and created new blood system with mutated CCR5. When exposed to HIV, recipients beat it back.
Status progressing towards IND enabling studies for scale up cell processing;
no imp-act on timelines or budget; clinical dev advisor meeting planned for Q4 2012
Back up
Eye Disease
Award
DR-1444 USC, UCSB Univ. College London (UK) TR-1219 Scripps Res. Institute TR-1272 UCLA
Goal
IND
Disease
Age-related Macular Degeneration (Dry form) Age-related Macular Degeneration (Dry form) Age-related Macular Degeneration (Dry form)
Approach
Allogeneic functionally polarized hESC-derived RPE monolayers on synthetic substrate implanted subretinally Autologous iPSC-derived RPE (generated without integrating vectors) Autologous adult SC (CMZ) or iPSCderived RPE +/- ex vivo engineering to express negative regulators of complement cascade
DC
DC
Eye Disease
Limbal epithelial stem cells reside in the basal layer of the epithelium, from GA Secker NCBI Bookshelf
Limbal stem cells
Award
TR-1794 UCI TR-1768 UCLA
Goal
DC POC
Disease
Retinitis Pigmentosa Limbal stem cell deficiency
Approach
Allogenic retinal progenitor cells Ex vivo expansion of corneal epithelial stem / progenitor cells also known limbal stem cells (LSC)
Cancer
Award
DR-1430 UC San Diego; Uni Health Network (Canada)
Goal
IND
Disease
Hematologic malignancy (AML, CML, ALL, CLL)
Approach
Existing candidate molecules (3 small molecule, 3 MAb) targeting leukemic stem cells (LSC) by blocking survival and self-renewal pathways that function preferentially Monoclonal antibody against CD47 Dont eat me antigen that is expressed on LSC and inhibits their phagocytosis by macrophages
IND
Cancer
A small-molecule drug selectively kills tumor cells by activating p53 protein, from www.cancer.med.umich.edu
Award
TR-1789 UCSD TR-1816 Children;s Hospital of L.A.; Univ. of Jena (Germany)
Goal
DC DC
Disease
Hematologic malignancy (CML) Hematologic malignancy (AML, ALL)
Approach
Small molecule pan BCL-2 inhibitor targeting LSC Small molecule inhibitor of BCL6 targeting LSC
Cancer
A confocal image showing -crystallin (green), a small heat shock protein in the perinuclear Golgi in dividing human U373 glioblastoma cells, from S.P. Bhatt UCLA
Award
DR-1477 UCLA; Stanford Univ., USC, Univ. Health Network (Canada)
Goal
IND
Disease
Solid tumors (Colon cancer, ovarian cancer, glioblastoma)
Approach
Small molecules specific for either of two drug targets in cancer stem cells (CSC)
Cancer
Award
DR-1421 City of Hope Med. Center DR-1426 UCSF, Ludwig Instit. for Cancer Res., SanfordBurnham Instit. for Medical Res. TR-1791 UCLA
Goal
IND
Disease
Recurrent Glioblastoma
Approach
Allogeneic established hNSC line to target tumor, engineered ex vivo to deliver carboxylesterase to locally convert CPT-11 to SN-38 Allogeneic hNSC (hMSC) to target tumor, engineered ex vivo to deliver a tumorcidal gene product (TRAIL or cytosine deaminase, and a suicide gene) Tumor homing by MSC genetically engineered to produce replication competent retrovirus encoding a suicide gene
IND
Recurrent Glioblastoma
DC
Cardiovascular
Award
DR1-01461 Cedars-Sinai Med. Center
Goal
IND
Disease
Advanced Ischemic Cardiomyopathy (heart failure) Multiple (Stroke, Heart disease, Skin ulcers, Bone fractures)
Approach
Autologous cardiac derived, cardiospheres, expanded and delivered by direct catheter injection into heart muscle Recombinant Wnt in a sustained release formulation to stimulate endogenous stem cells to repair tissues
DC
Goal
IND
Disease
ALS
Approach
Allogeneic hESC-derived astrocyte precursors delivered into spinal cord (delivery device) The best of either hNSC derived from tissue, ESC, or iPSC; or hVM (ventral mesencephalon) precursors derived from ESC, NSC, or tissue
TR1-01267 Sanford-Burnham Institute; Howard Florey Institute (State of Victoria, AS) TR2-01856 Buck Institute; City of Hope National Medical Center
DC
Parkinsons Disease
DC
Parkinsons Disease
POC
Parkinsons Disease
Small molecule modulator of neuroinflammation identified by screening on astrocytes/microglia from patient-derived iPSCs
Award
TR1-01245 UCI, Monash University (State of Victoria, AS)
Goal
Disease
Approach
Allogeneic hESC-derived NSC or hESC-derived NSC genetically modified with a beta-amyloid degrading enzyme or a transcription factor that promotes neuronal differentiation for transplantation Allogeneic MSC engineered ex vivo to express siRNA targeting mutant huntingtin mRNA. Injected intracranially Allogeneic hESC-derived neural stem or progenitor cells for transplantation
DC
Alzheimers Disease
DC
Huntingtons Disease
DC
Huntingtons Disease
38
Neurological Disorders
Award
TR2-01785 UCLA DR1-01480 Stanford University, UCLA TR2-01767 UCI
Goal
POC
Injury
Spinal Cord Injury
Approach
Allogeneic hESC-derived motor and autonomic precursor neurons Allogeneic hESC-derived NSC line transplanted alone or in combination with matrix
IND
Stroke
POC
Neurological Disorders
Award
TR2-01844 iPierian, Inc. TR2-01832 City of Hope National Medical Center, University of Bonn (BMBF, Germany)
Goal
DC
Disease
Spinal Motor Atrophy
Approach
Small molecule that increases SMN1 gene product in patient iPSCderived motor neurons Autologous iPSC-derived neural or oligodendrocyte progenitors, genetically modified to correct mutant (aspartoacylase) ASPA gene Neurons from ASD (and control) iPSC for phenotype screening, assay development and validation, drug screening and biomarker identification Allogeneic hESC-derived progenitors from GABAergic inhibitory neurons analogous to those in medial ganglionic eminence
POC
Canavan Disease
TR2-01814 UCSD
POC
TR2-01749 UCSD
POC
Refractory Epilepsy
Award
DR1-01423 ViaCyte Inc., UCSF
Goal
Disease
Approach
Allogeneic hESC-derived pancreatic cell progenitors in a device implanted subcutaneously that mature in vivo to beta cells that secrete insulin in response to glucose. Transient immunosuppression.
IND
Diabetes
DC
41
HIV/AIDS
Award
DR1-1431 UCLA, Calimmune, Inc. DR1-1490 City of Hope National Medical Center, USC, Sangamo Biosciences TR2-1771 City of Hope National Medical Center
Goal
Disease
AIDS Lymphoma
Approach
Autologous HSC transduced ex vivo with a lentiviral vector engineered to express a shRNA against CCR5 & fusion inhibitor. IV administration after myeloablation. Autologous HSC transduced ex vivo with non-integrating vector engineered to express zinc finger nuclease against CCR5. IV administration after myeloablation Autologous HSC genetically modified ex vivo with multiple anti-HIV resistance genes and a drug resistance gene
IND
IND
AIDS Lymphoma
DC
AIDS Lymphoma
Award
DR1-01452 UCLA, Childrens Hospital, LA TR1-01273 Salk Institute
DR1-01454 Stanford University
Goal
Disease
Sickle Cell Anemia
Approach
Autologous HSC, genetically corrected ex vivo by lentiviral vector mediated addition of a hemoglobin gene that blocks sickling. IV administration after myeloablation Autologous iPSC-derived HSC genetically corrected by homologous recombination
Epidermal sheets from expanded autologous genetically corrected (to express wild type COL7A1) iPSC-derived keratinocytes Autologous skeletal muscle precursor cells derived from human iPSCs genetically modified to correct the dystrophin gene
IND
DC
IND
POC
Regenerative Medicine CIRM researchers to be featured Pharma & Investor Premier event for regenerative medicine industry Partnering Conference Patent funding and Technology Transfer Support
$5 M allocated for technology transfer support; program being developed