Metabolic Disorders

Coding Dimension ID: 
393
Coding Dimension path name: 
Metabolic Disorders
Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-11478
Investigator: 
ICOC Funds Committed: 
$11 999 944
Disease Focus: 
Cystinosis
Kidney Disease
Kidney Failure
Metabolic Disorders
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

Autologous Human CD34+ HSC from Mobilized PBSC of Patients with Cystinosis Modified by Ex Vivo Transduction using the pCCL-CTNS Lentiviral Vector

Indication

Cystinosis - An autosomal metabolic disease that belongs to the family of the lysosomal storage disorders. Gene involved is CTNS (encodes cystinosin).

Therapeutic Mechanism

The proposed therapy intervention is intended to impact the target indication of Cystinosis via autologous tranplantation of CD34+ HSC-mediated transfer of a functional cDNA using pCCL-CTNS lentivirus vector. The gene-corrected HSC progeny will differentiate into macrophages in injured tissues and transfer cystinosin-bearing lysosomes via Tunneling Nanotubes (TNTs) to disease cells. This transfer of functional cystinosin to endogenous tissue cells leads to long-term tissue preservation.

Unmet Medical Need

The only treatment available for cystinosis is a lifetime oral cysteamine, with severe side effects and compliance challenges, that only delays the disease complications. This approach may represent a one-time life-long therapy that may prevent kidney transplantation and quality of life of patients.

Project Objective

Phase 1/2 trial completed

Major Proposed Activities

  • Clinical:
    - Screening and Enrollment
    - Product Administration
    - Clinical Monitoring/Safety Assessments by DSMB (IQVIA)
    - 24-month Patient Follow-Up
  • Manufacture clinical product for the proposed trial:
    - Mobilization and Leukapheresis
    - CD34+ Isolation & Transduction
    - Release Testing & Infusion
Statement of Benefit to California: 

California has approximately 20 cystinosis patients, and their families, who could directly benefit from this treatment. Financial burden on MediCal is expected to by reducing or eliminating the costs of Cysteamine and the treatment cost of secondary conditions such as hypothryodism, polyurea, etc (cost range per patient ~$300,000-600,0000/year). Moreover, at least 80% of the funds spent will be within the state of California.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-11437
Investigator: 
ICOC Funds Committed: 
$11 083 012
Disease Focus: 
Diabetes
Metabolic Disorders
Type 1 diabetes
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

Human pancreatic islets and parathyroid gland combination graft

Indication

Patients with established Type 1 diabetes

Therapeutic Mechanism

Pancreatic islet transplantation has become a more viable approach to treat patients with established Type 1 diabetes. However, widespread application has been limited by several barriers, most importantly, poor islet survival and an inability to monitor islets after transplant. Co-transplantation of parathyroid tissue with pancreatic islets leads to dramatic improvement in islet survival and function after intramuscular transplant, which enables easy access and monitoring.

Unmet Medical Need

The ability to restore long-term normal blood glucose levels with islets from a single donor, using a low morbidity procedure, in a retrievable site that can be non-invasively monitored has not been attainable previously. The PARADIGM trial is aimed at addressing this critical unmet need.

Project Objective

Phase I/IIa trial completed

Major Proposed Activities

  • Perform phase I/IIa safety and efficacy trial of pancreatic islet and parathyroid co-transplantation in the muscle of patients with Type 1 diabetes
  • Perform safety analysis and efficacy assessment of islet and parathyroid grafts in a novel intramuscular islet transplant site
  • Perform exploratory studies on islet engraftment mechanisms and immunologic monitoring of pancreatic islet and parathyroid grafts
Statement of Benefit to California: 

Diabetes affects 2.3 million Californians with annual healthcare costs of over $12 billion. If successful, this work can lead to a more effective therapy that directly benefits patients with Type 1 diabetes and those who are on insulin therapy. By developing a retrievable transplant site, it also paves the way for future clinical translation of stem cell-derived islets that can potentially invigorate research and biotechnology development in California.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-09730
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$12 211 255
Disease Focus: 
Diabetes
Metabolic Disorders
Type 1 diabetes
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

Autologous Ex Vivo Expanded Polyclonal CD4+CD25+CD127lo/-FOXP3+ Regulatory T-cells (CLBS03)

Indication

Early Onset Type 1 Diabetes Mellitus with Residual Beta Cell Function

Therapeutic Mechanism

It must be acknowledged that the mechanism(s) by which the effector arm of the immune system becomes unrestrained in the setting of T1D, resulting in the immune destruction of pancreatic beta-islet cells, is not known at this time. Available evidence indicates that Tregs maintain immune balance by modulating multiple facets of the effector arm of the immune system at least in part by control of differentiation of multipotent progenitor/stem cells.

Unmet Medical Need

No therapy aimed at maintaining or restoring pancreatic beta islet cell function is currently approved for Type 1 diabetes mellitus (T1D). As a result children with T1D face lifelong struggles with glycemic control and, despite careful management, an increased risk of severe complications.

Project Objective

Phase 2 trial completed

Major Proposed Activities

  • Enrollment and treatment of the remaining 92 subjects in the phase 2 clinical trial
  • Manufacturing investigational product for the remaining subjects in the trial
Statement of Benefit to California: 

All cell manufacturing for this study will be performed in California. Accordingly this project will have an immediate positive effect on employment of highly skilled workers in California. The demonstration of preservation of beta-islet cell function, with attendant reductions in exogenous insulin requirements, would provide compelling clinical evidence to advance this therapy and would provide strong momentum toward advancing a cure of T1D. Such a cure would benefit California and the world.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-09672
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Diabetes
Metabolic Disorders
Type 1 diabetes
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

pancreatic progenitor cells in a delivery device that allows direct vascularization

Indication

high-risk type 1 diabetes including "brittle" diabetes and hypoglycemia unawareness

Therapeutic Mechanism

People with type 1 diabetes have lost their pancreatic cells that make insulin, and therefore have to self-administer insulin. It is very difficult to manage blood sugar to safe levels by this method. Chronically too high can lead to blindness, kidney failure, nerve damage, and heart problems, and too low can cause coma or death. This product will replace the lost pancreatic cells and provide a natural biological ability to maintain stable healthy blood sugar levels.

Unmet Medical Need

There are over 100,000 people in the US with type 1 diabetes so severe that they are at constant risk of hospitalization and/or death. Within months after administration, this product could naturally restore those patients’ blood sugar to normal healthy levels and save their lives.

Project Objective

Phase 1/2 trial completed

Major Proposed Activities

  • Manufacture and quality control of the test article for clinical trial
  • Launch and run clinical trial
  • Assay development
Statement of Benefit to California: 

The product will be available through clinical trials in California and if approved by the FDA for commercial use, will help many thousands of Californians with high-risk diabetes. The product will save lives and increase quality of life for patients/families, while significantly reducing the state's health care burden. Indeed the product could become the most significant stem cell-based medical treatment of the coming decade; a tremendous achievement for California, its taxpayers, and CIRM.

Grant Type: 
Accelerated Development Pathway I
Grant Number: 
AP1-08039
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$16 603 160
Disease Focus: 
Diabetes
Metabolic Disorders
Type 1 diabetes
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 

We are developing a stem cell-derived replacement cell therapy for insulin-requiring diabetes. Through a process known as directed differentiation, embryonic stem cells are turned into pancreatic cells in the laboratory. The pancreatic cells are loaded into a delivery device, which is essentially a small envelope made with a semi-permeable membrane, not unlike a flat tea bag. When the cells in the device (combination product) are implanted under the skin, they become pancreatic endocrine cells, including insulin-producing beta cells that respond to elevated blood glucose by releasing insulin in a physiologic manner. The prototype combination product has been tested in hundreds of animals, is routinely curative in a mouse model of chemically-induced diabetes, and has been shown to be safe in several animal studies. Moreover, the delivery device has been shown to protect cells from a recipient’s immune system. The Team has received valuable feedback from the FDA, and we plan to launch the first clinical test of our therapeutic candidate in patients with diabetes in 2014. This first clinical trial will utilize the prototype to establish safety in humans, and determine the dosing range that might provide benefit to patients with diabetes.

The current application is to fund additional clinical research, and associated product development activity, that will (1) ensure the first trial is executed in a most informative and timely fashion, (2) accelerate the pace at which information is collected on how the product works in humans – testing various formats, and in different types of patients – and (3) substantially increase the likelihood that the most appropriate format and patient population is selected for a definitive “Phase 3” clinical trial. A Phase 3 trial serves as the basis for an application to the FDA to obtain a license to market the product. In this way, CIRM Accelerated Development Pathway designation of the project will substantially increase the probability that, and pace at which, this product concept becomes a real treatment available to the millions of patients in need.

Statement of Benefit to California: 

Diabetes mellitus currently afflicts approximately 370 million people worldwide, with projections of over 550 million by the year 2030 (sources: World Health Organization; International Diabetes Federation). In the year 2000 there were approximately 2 million cases of diabetes in California (source: Diabetes Control Program, California Department of Health Services). Further, the disease disproportionately affects certain minority groups and the elderly. Despite the use of insulin and advances in its delivery, the human cost of diabetes is underscored by the financial costs to society: tens of billions of dollars each year in California alone. The primary cause of type 1 diabetes, and contributing significantly to type 2 diabetes as well, is the loss of insulin-producing pancreatic beta cells. The CIRM Diabetes Disease Team Project is developing an innovative beta cell replacement therapy for insulin-requiring diabetes. If successful, the therapy will go beyond insulin function, and will perform the full array of normal beta cell functions, including responding in a more physiological manner than manual or mechanized insulin self-administration. Because they will be more physiological, the replacement cells could reduce the long-term effects of diabetes. Moreover, the cell therapy will alleviate patients of the constant monitoring of blood glucose, painful insulin injections, and the ever-present risk of overdosing with insulin. For these reasons, it is possible that the product could transform the diabetes treatment landscape dramatically and even replace pharmaceutical insulin in the market. This product will be available in California first, through clinical testing, and if approved by the FDA for commercial production, will eventually help hundreds of thousands of Californians with diabetes. The product will substantially increase quality of life for patients and their families, while significantly reducing the health care burden in the state. The proposed project will employ Californian doctors and scientists, and success will prove highly noteworthy for the state. Lastly, once commercially marketed, the product will yield additional jobs in manufacturing, sales, and related industries, and generate revenue for California. Given the market need and the clear feasibility, the product could become the most significant stem cell-based medical treatment of the coming decade, and that will be a tremendous achievement for California, its taxpayers, and CIRM.

Grant Type: 
Strategic Partnership I
Grant Number: 
SP1-06513
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$10 075 070
Disease Focus: 
Diabetes
Metabolic Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

Diabetes exacts a tremendous toll on patients, their families, and society. Autoimmune Type 1 diabetes, often called juvenile-onset diabetes, is caused by a person’s own immune system mistakenly destroying their insulin-producing cells in the pancreas, known as beta cells. When those beta cells are lost, the ability to produce insulin in response to consumed carbohydrates is lost, and blood sugar can increase to toxic levels. Although not due to autoimmunity, Type 2 diabetics often lose their ability to produce insulin as well. While pharmaceutical insulin is commonly used to control both types of diabetes, it is difficult to self-administer optimally, does not sufficiently replace beta cells, and the adverse short- and long-term effects of diabetes and risks associated with insulin usage remain, including potentially fatal hypoglycemic episodes, nerve damage, blindness, kidney failure, foot ulcers / amputations, and heart disease.

Ideally, one would like to replace lost beta cells, and attempts to do so have included the use of pancreas transplants, beta cell (islet) transplants, and transplants of animal cells. Unfortunately, those approaches are hindered by 1) a limited amount of donor tissue, and 2) issues regarding immunological incompatibility between donors and recipients. To solve the first problem, the group applying for this CIRM award has developed methods to make replacement beta cells from human embryonic stem cells (hESC), which can be reliably grown in large-scale batches. The hESC-derived beta cells have been shown to cure experimental diabetes in mice and rats. Regarding the issue of donor-recipient compatibility, the group has found that the cells can be administered under the skin in a simple device, essentially an envelope made of semi-permeable membrane, which is intended to protect the implanted cells from the patient’s immune system. Upon implant, the cell-loaded device, which also keeps the implanted cells in place, acquires its own dedicated circulation. This blood supply provides oxygen and nutrients to the implanted cells, and also allows them to respond to blood sugar by releasing pancreatic hormones such as insulin into the circulation. Thus, the implanted cell-loaded device in essence represents a “replacement endocrine pancreas” with its own protection from autoimmunity. This product could return a patient's blood sugar regulation to normal and alleviate both the day-to-day and long-term issues of diabetes.

The group has made tremendous progress in moving the product from concept through years of research and development. At this point an array of detailed work on the exact format to be tested in humans needs to be completed and submitted to the FDA on the way to clinical trials. The proposed award would provide critical funding, including potentially triggering matching funding from a large corporate partner, to advance the product through the first-in-human testing which will be very informative.

Statement of Benefit to California: 

Diabetes mellitus currently afflicts approximately 350 million people worldwide, with projections of over 500 million by the year 2030 (sources: World Health Organization; International Diabetes Federation). In the year 2000 there were an estimated 2,089,657 cases of diabetes in California (diagnosed + undiagnosed; source: Diabetes Control Program, California Department of Health Services). Further, the disease disproportionately affects certain minority groups and the elderly. Despite the use of insulin and advances in its delivery, the human cost of diabetes is underscored by the financial costs to society: tens of billions of dollars each year in California alone. The primary cause of Type 1 diabetes, and contributing significantly to Type 2 diabetes as well, is the loss of insulin-producing pancreatic beta cells. The proposed Partnership will develop a beta cell replacement therapy for insulin-dependent diabetes. If successful, the therapy will go beyond insulin function, and will perform the full array of normal beta cell functions, including responding in a more physiological manner than manual or mechanized insulin administration. Because they will be more physiological, the replacement cells should also reduce the long-term effects of diabetes. Moreover, the cell therapy will alleviate patients of the constant monitoring of blood glucose and painful insulin injections. For these reasons, it is possible that the product could transform the diabetes treatment landscape dramatically and even replace pharmaceutical insulin in the market. This product will be available in California first, through clinical testing, and if approved by the FDA for commercial production, will eventually help hundreds of thousands of Californians with diabetes. The product will substantially increase quality of life for patients and their families while significantly reducing the health care burden in the state. The proposed Partnership will employ Californian doctors and scientists, and success will generate accolades and notoriety for the state. Lastly, once commercially marketed, the product will yield additional jobs in manufacturing, sales, and related industries, and generate revenue for California. Given the market need and the clear feasibility, the product could become the most significant stem cell-based medical treatment of the coming decade, and that will be a great achievement for California, its taxpayers, and CIRM.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-14090
Investigator: 
ICOC Funds Committed: 
$2 296 920
Disease Focus: 
Autism
Intellectual Disability
Metabolic Disorders
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

The objective is to define a final therapeutic candidate for an effective gene therapy for mutations of the creatine transporter SLC6A8, a major cause of X-linked intellectual disability (ID).

Impact

This disorder results in severe ID, autistic-like behavior, seizures, & lack or delay of speech with no treatment. Improving brain transduction is essential and widely applicable to other conditions.

Major Proposed Activities

  • Develop multiple adeno-associated viral (AAV) vectors expressing human SLC6A8, package, determine titers and expression in human induced pluripotent stem cell (hiPSC)-derived neurons in vitro.
  • Assess resolution of any deficits and improvement in creatine transport in SLC6A8-mutated hiPSC-derived neurons by vector-mediated expression.
  • Assess transduction efficiency of AAV-SLC6A8 in vivo with brain cell expression and distribution of vector copies and tissue creatine levels in non-brain organs and tissues in Slc6a8-mutated mice.
  • Assess disease modifying activity of AAV-SLC6A8 in the a murine Slc6a8-mutated model.
  • Determine final therapeutic candidate, complete draft target product profile, and develop assays of purity, activity and identity.
  • Request INTERACT meeting.
Statement of Benefit to California: 

Genetic-based intellectual disability of all causes is a more common occurrence than is appreciated. Effective therapies for these intellectual disabilities, where often there are none, could improve the lives of thousands of afflicted Californians & their families along with many hundreds of thousands of afflicted people worldwide. Brain gene therapy may result in novel, effective treatments for these disorders & improvement in their quality of life, with applicability to other conditions.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-13498
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 198 550
Disease Focus: 
Diabetes
Metabolic Disorders
Type 1 diabetes
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Research Objective

We will generate nanoprobe-containing stem cell-derived human beta cells that can be monitored in real time in response to inflammatory stress upon transplantation in patients with type 1 diabetes.

Impact

Our product will replace donor islets for cell replacement therapy in patients with type 1 diabetes, and will provide a readout of cell survival and an opportunity for therapeutic intervention.

Major Proposed Activities

  • Test insulin-producing cell organoids with nanosensors to secrete insulin in response to elevated glucose and emit a signal in real time, and test similar activities in animal models of diabetes.
  • Test the ability of insulin-producing cell organoids with nanosensors to emit a measurable signal in response to increased inflammation in vitro and after transplantation in small animal models
Statement of Benefit to California: 

The American Diabetes Association states that California, with the highest number of patients with diabetes in the country, also has the highest cost at $39.47 billion. A large proportion of these patients are insulin-dependent and are potential candidates for islet replacement therapy. Developing technologies that can improve transplantation outcomes in patients directly affects long-term quality of life. All Minutia staff are CA residents, with a long history of collaboration with UCSF.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-13441
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$776 340
Disease Focus: 
Intestinal Disease
Metabolic Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

Research Objective

We propose to discover a tool that will utilize patient specific iPSC-derived human mini-guts to identify personalized antifibrotic treatments in pediatric Crohn’s disease patients

Impact

The major bottleneck in intestinal fibrosis research is the difficulty in obtaining patient-specific biologically relevant cells for in vitro modeling. This iPSC-derived tool would overcome it.

Major Proposed Activities

  • Procurement of patient specific cells from pediatric Crohn's disease patients that have intestinal fibrosis (Months 0-3)
  • Reprogram each patients harvested cells to form induced pluripotent stem cells (month 3-9)
  • Determine compounds via high throughput screening that attenuate the fibrotic response in each patient’s iPSC-derived cells (Months 9-15)
  • Validation of candidate compounds in corresponding biopsy-derived cells (Months 15-18)
  • Transcriptomic analysis between paired iPSC-derived cells and biopsy derived cells (Months 18-24)
Statement of Benefit to California: 

Crohn's disease is a recurring inflammatory disorder that affects the intestine, and the number of patients that suffer from this in the US continues to rise each year. There are numerous patients who have Crohn's disease in California and 20-30% of these patients will require surgery due to intestinal fibrosis. There is no therapy to prevent or treat this but the tool proposed would establish a platform that would allow numerous therapies to be tested in a personalized manner

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-13213
Investigator: 
ICOC Funds Committed: 
$1 523 285
Disease Focus: 
Diabetes
Metabolic Disorders
Type 1 diabetes
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

Determine optimal islet transplant conditions and systemic treatments that promote graft survival upon transplantation into immune-competent diabetic subjects.

Impact

Our proposal will optimize the generation and viability of an unlimited, reproducible source of human engineered islets for transplantation.

Major Proposed Activities

  • Demonstrate improved HILO graft survival with FGF1 coating
  • Prolong grafted HILO survival by reducing metabolic insulin demand
Statement of Benefit to California: 

Diabetes affects 3 million people in California. Type 1 diabetes is a particular burden as it requires life-long administration of insulin. Allo-transplantation of islets is limited by availability of donor cells. This proposal will facilitate the generation of functional ESC-derived islet-like organoids as an unlimited, reproducible source and optimize methods to increase functionality and viability upon transplantation into diabetic patients.

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