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

Therapeutic Candidate or Device

Combined hematopoietic stem cell graft and recipient T regulatory cells

Indication

Kidney disease requiring kidney transplantation

Therapeutic Mechanism

The study will determine whether patients treated with TLI and rATG, and given a haploidentical living donor hematopoietic progenitor cell transplant (HSCT) , along with in vitro expanded recipient Treg cells (what we term as combinatorial therapeutic cell therapy) can achieve sustained donor mixed chimerism and be withdrawn from immunosuppressive drugs while maintaining normal renal function after renal transplantation.

Unmet Medical Need

The goal is “one kidney for life” off drugs with safety for all patients. The overall health status of patients off IS drugs will improve due to reduction in side effects associated with IS drugs, and due to reduced graft loss afforded by tolerance induction that will prevent chronic rejection.

Project Objective

Phase 1 trial completed

Major Proposed Activities

• Assessment and adjustment of the Treg dose required to sustain chimerism in the recipients without causing adverse reactions such as GVHD
• Assessing the impact of immunosuppressive drug dose reductions toward withdrawal without graft rejection or adversely affecting kidney function
• Assess kidney duration post-transplant compared to patients undergoing SOC kidney transplants w/out cell therapy to induce immune tolerance

Therapeutic Candidate or Device

MDR-101 is cellular therapy consisting of kidney donor-derived CD34+ HSCs and CD3+ T-cells.

Indication

Maintenance of kidney allograft function after withdrawal of post-transplant immunosuppressant (IS) drugs in HLA matched kidney transplants recipients

Therapeutic Mechanism

Following infusion and engraftment of MDR-101, the progeny cells establish a state of mixed lympo-hematopoetic chimerism. This leads to a condition known as immune tolerance in which the transplanted kidney is no longer viewed as foreign by the recipient. This allows the gradual withdrawal of all immunosuppressive (IS) drugs that were previously required to prevent rejection of the transplanted kidney

Unmet Medical Need

It is well established the current IS drugs are directly nephrotoxic and have increased risks of diabetes, heart disease, and cancers and contribute to increased transplant recipient morbidity and mortality and coincident transplant organ loss. Elimination of IS drugs should minimize these risks.

Project Objective

Completion of P3 study and BLA submission to FDA

Major Proposed Activities

• cGMP manufacturing of MDR-101 product
• Demonstrate predictive value of donor mixed chimerism testing in recipients of HLA matched HSCs
• Demonstrate the ability to achieve durable immune tolerance

Therapeutic Candidate or Device

blood stem cells and T cells from organ transplant donors will be studied under this proposal to prevent rejection of kidney transplants

Indication

to withdraw immunosuppressant drugs from kidney transplant recipients

Therapeutic Mechanism

Injection of the donor blood stem cells into recipients will prevent recipient immune cells from rejecting the donor kidney transplant.

Unmet Medical Need

The proposed treatment eliminates the life long need of immunosuppressive drugs to prevent kidney transplant rejection. Immunosuppresive drugs increase the risks of cancer, infection, and heart disease.

Project Objective

Phase 1 trial completed

Major Proposed Activities

• Manufacture of the optimum donor cell product for injection into kidney transplant recipients
• Assess the clinical safety of the donor cell injection
• Assess the ability of the donor cell injection to eliminate the need for life long immunosuppressive drugs

Therapeutic Candidate or Device

Human Acellular Vessel (HAV)

Indication

Conduit for Vascular Access for Hemodialysis

Therapeutic Mechanism

Mechanism of action: the HAV is comprised of intact extracellular matrix constructed by human smooth muscle cells (SMC) in a biomimetic bioreactor system. The manufacturing process is designed to create a biologic matrix similar in protein composition and 3 dimensional structure with biomechanical properties that are observed with native tissue. Once implanted, the HAV is remodeled by the host resulting in a vascular structure more similar in histological appearance to native vascular tissue.

Unmet Medical Need

Current vascular access technologies for hemodialysis are fraught with complications associated with thrombosis, infection and abandonment. Compared to conventional vascular access treatments for dialysis the HAV has the potential for less frequent clotting, abandonment and infection.

Project Objective

Completion of Phase III Clinical Program

Major Proposed Activities

• Manufacturing & Distribution of the HAV for clinical testing in dialysis patients
• Enrollment in Phase III Clinical Trial and Implantation of HAV into patients requiring vascular access for hemodialysis
• Longitudinal test subject follow-up, data collection and analysis, regulatory approval of HAV for widespread clinical use

Therapeutic Candidate or Device

Human Acellular Vessel (HAV)

Indication

Conduit for Vascular Access for Hemodialysis

Therapeutic Mechanism

Mechanism of action: the HAV is comprised of intact extracellular matrix constructed by human smooth muscle cells (SMC) in a biomimetic bioreactor system. The manufacturing process is designed to create a biologic matrix similar in protein composition and 3 dimensional structure with biomechanical properties that are observed with native tissue. Once implanted, the HAV is remodeled by the host resulting in a vascular structure more similar in histological appearance to native vascular tissue.

Unmet Medical Need

Current vascular access technologies for hemodialysis are fraught with complications associated with thrombosis, infection and abandonment. Compared to conventional vascular access treatments for dialysis the HAV has the potential for less frequent clotting, abandonment and infection

Project Objective

Completion of Phase III Clinical Program

Major Proposed Activities

• Manufacturing & Distribution of the HAV for clinical testing in dialysis patients
• Enrollment in Phase III Clinical Trial and Implantation of HAV into patients requiring vascular access for hemodialysis
• Longitudinal test subject follow-up, data collection and analysis, regulatory approval of HAV for widespread clinical use

Research Objective

AAV-SPL 2.0 is a gene therapy cure for SPLIS, a lethal childhood disorder of metabolism that causes kidney failure. Our gene therapy may also work in more common fibrotic (scarring) kidney diseases.

Impact

Our treatment may cure a rare but often fatal genetic disease (SPLIS) for which no specific treatment is available. It may additionally cure other forms of kidney disease caused by kidney scarring.

Major Proposed Activities

• Test the ability of our gene therapy to prolong survival in a newborn mouse model of SPLIS.
• Test the ability of our gene therapy to protect the kidney from damage in an adult mouse model of SPLIS.
• Test the ability of our gene therapy to protect the kidney from damage in mouse models of more common forms of kidney fibrosis.
• Use mouse models to demonstrate where in the body our gene therapy can reach and restore the activity of the enzyme encoded by the gene.
• Test the ability of the gene therapy to restore sphingolipid metabolism in mouse models of SPLIS

Research Objective

Approximately 20,000 babies are born annually with kidney disease; the long-term outcome is poor. These studies address new ways to develop mini-kidney structures for transplantation to induce repair.

Impact

~85% of people on the organ waitlist are in need of a kidney and there are insufficient donors. There is a pressing need to identify methods for repair that avoid the need for an organ transplant.

Major Proposed Activities

• Address a way to create mini-organs in 3D using growth factors, a biodegradable scaffold, and cell differentiation techniques that recapitulate kidney development and the required cell interactions.
• Investigate the interactions between cells that induce each other by layering components and determining if structures needed are enhanced, and in a rigorous and reproducible manner.
• Compare in a quantitative and qualitative manner the characteristic features required such as branching in layered 3D structures and the capabilities of cells to self-organize, interact, and mature.
• Evaluate the effects of oxygen in the culture environment in which the cells and future mini-kidneys are grown to determine if the structures are enhanced and necessary vessels form.
• Identify a candidate kidney construct with the necessary elements for future transplantation in a translational animal model of congenital kidney disease.
• Publish the results and share outcomes on the CIRM and related websites.

Translational Candidate

LXW7 coated ePTFE vascular graft achieves rapid endothelization and improved graft patency by capturing endogenous endothelial progenitor cells

Area of Impact

This technology will produce long-lasting vascular grafts with self-renewable “living” endothelium and improve dialysis patients’ quality of life

Mechanism of Action

The arteriovenous ePTFE dialysis graft approach is the most common form of vascular access for hemodialysis in the U.S., but has high failure rates. One of the major causes is the lack of a functional endothelium which is crucial to the prevention of thrombosis and stenosis. The LXW7 coated ePTFE graft will promote in situ endothelialization as the LXW7 works to increase the capture and binding of endogenous endothelial progenitor cells (EPCs) and endothelial cells (ECs)

Unmet Medical Need

Globally, in 2018 it was estimated that there were over 2 million people who suffered from kidney failure. Patients undergoing hemodialysis often require multiple interventions due to graft failure. There is an unmet clinical need for long-term vascular access for hemodialysis patients.

Project Objective

Pre-IDE meeting with the FDA

Major Proposed Activities

• Manufacture, characterize, and optimize a viable prototype in making LXW7-ePTFE grafts and evaluate their properties in vitro
• Evaluate the mechanism of action, function, and efficacy of LXW7-ePTFE grafts in small animal models
• Investigate the short-term and long-term behavior and function of LXW7-ePTFE grafts in clinically relevant large animal models