Early Translational IV
$1 659 171
We propose to develop a bioengineered, implantable Thymus gland to treat patients who suffer from diseases caused by immune deficiency. A healthy immune system is essential to prevent infections, cancer and autoimmune diseases such as diabetes, rheumatoid arthritis and inflammatory bowel disease. The Thymus converts blood-forming stem cells into T cells that protect against infection and cancer, but which have also been “educated” to not react against normal tissue and cause autoimmune disease. With aging, the Thymus shrinks, and normal T cell production falls. The problem is even worse in patients who have had chemotherapy or viral infections such as HIV. The most severe form of thymic insufficiency is in babies in which the thymus never develops, a lethal condition called Di George Anomaly (DGA). Our team has devised a novel method to produce a human thymus that can be surgically implanted. We culture different components of the human thymus and engineer them to enhance their growth and function. We have shown that after implantation into mice, the new thymus can produce functional human T cells. Our first goal is to scale-up the method for clinical treatment of babies with DGA. We then plan to broaden the application of this technology by producing Thymic implants from induced pluripotent stem cells, providing an inexhaustible supply of matched tissue for treatment of a variety of immune deficiencies and autoimmune diseases that arise in adult life.
Statement of Benefit to California:
The goal of this proposal is to develop a bioengineered thymus gland to provide an environment for the production and control of a healthy immune system. Immune dysfunction provides the catalyst for many of the major chronic diseases that plague our society. Each year, tens of thousands of Californians are diagnosed with autoimmune diseases such as Type I Diabetes, Multiple Sclerosis, Systemic Lupus Erythematosus and rheumatoid arthritis. Over 21,000 Californians and 100,000 Americans are estimated to be in need of organ donation for life threatening diseases. Heavy suppression of the immune system is required to prevent rejection of transplanted organs resulting in many serious side effects for patients. For the thousands of patients who undergo bone marrow transplantation for leukemia and genetic diseases, the most common problem is immune-mediated graft versus host disease which in turn damages the thymus and leads to life threatening infections. We propose an entirely novel approach to regenerate the damaged thymus, by providing a microenvironment that can be engineered to control the immune system after surgical implantation.
The objective of this Development Candidate Feasibility Award proposal is to develop engineered human thymic tissue implants for the treatment of congenital athymia (diGeorge anomaly) and other diseases resulting from thymic insufficiency. It is envisioned that after implantation, the endogenous blood forming stem cells will home to the engineered thymic tissue and produce the functional T cells that are missing in the targeted disease. The applicants initially plan to utilize post-natal allogeneic thymic tissue for the scale up of method for clinical applications but eventual goal is derivation of two main cell types of the thymus from autologous induced pluripotent stem cells (iPSCs) providing renewable source of matched tissue for the treatment of number of immune deficiency diseases. The applicants also suggest that the thymic implant could also be useful to induce T cell tolerance in disorders where autoreactive T cells are implicated. Objective and Milestones - The Target Product Profile is sufficiently reasonable. - Project milestones address some but not all of the key activities required to achieve proof of concept. The success criteria and go/no-go decision points are not sufficiently described. Rationale and Significance - Development of functional thymic implant could have immediate impact on the intended immune deficiency disease and has potential for significant impact on other immune deficiency diseases although clinical translation would require further proof of concept well beyond what is proposed in the application - Reviewers found preliminary data to be supportive of the proposed research but insufficient as key information to evaluate the functionality of the product is absent. Feasibility and Design - Reviewers were not convinced that the aims of the project could be achieved in 3 years. - Research plan for the project contains some elements that would contribute to moving the field forward, but lacks several critical experiments that would be needed to provide convincing proof of concept. For example, very limited work is proposed for optimizing thymic epithelial cell culture conditions as it relates to determining the potency of individual cell types. Important questions of what extent tolerance induction (negative selection and Treg production) occurs in the thymic implants and the longevity of the implants and how it relates to output of naïve T cells in numerical terms are not addressed. No indication is given to how specific ECM proteins expressed in the thymus will be identified or how their distribution will be determined. - Reviewers raised major concern regarding vascularization of the tissue inside the proposed scaffold and were not convinced that the expression of the growth factor alone would be enough to address this issue. Applicants did not provide reasonable alternative approaches in case the proposed bioengineered scaffold fails. - Insufficient attention is paid to assess the functionality of the engineered thymic tissue with respect to negative selection and induction of tolerance. - Reviewers found Aim 3 (the portion of the research plan focused on the derivation of functional thymic cells from pluripotent cell sources) premature and speculative and lacking details of the development of individual components that will be needed to assemble a fully functional and non-immunogenic engineered allograft. The inclusion of Aim 3 is not fully justified scientifically, though it does increase the responsiveness of the proposal. Elimination of this aim would make the research plan more feasible within the timeframe. - No studies are proposed to support the suggestion that this therapy could be applied to induce tolerance to autoimmune disorders and disorder of the thymic deficiency. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI is a physician scientist with a strong track record in hematopoiesis and lymphoid cell development - The team contains the overall expertise required for the project. Inclusion of experts on thymic stromal cell biology, epithelial cell culture and functional validation would strengthen the project team Collaborations, Assets, Resources and Environment - The collaborations appear to be appropriate and provide needed expertise. - The available resources are excellent Responsiveness to the RFA - While novel, the first component of the proposal is not highly responsive to the RFA, as it does not require stem cells or iPSC to succeed. The second component utilizes iPSC and is thus responsive to the RFA