Systemic Gene Therapy for Tuberous Sclerosis

Principal Investigator: BREAKEFIELD, XANDRA O
Program: TSCRP
Proposal Number: TS150045
Award Number: W81XWH-16-1-0134
Funding Mechanism: Exploration - Hypothesis Development Award
Partnering Awards:
Award Amount: $240,037.00


There is a pressing need to develop new therapies for patients with tuberous sclerosis complex (TSC). Current drug therapies have a number of limitations, including: expense; need to continuously take medications; side effects, including reduced immune function; and possible interference with normal development of the brain. Gene therapy is a new medical therapy that can be implemented with only a single application, has low-to-no side effects, and has proven benefit in several human diseases.

Symptoms in TSC are caused by loss of function of proteins, hamartin (in TSC1) or tuberin (in TSC2), in tissues throughout the body, leading to enlarged size of cells and overgrowths of tissue. Using a vector that has proven safe in clinical trials, it should be possible to replace the missing protein in many affected cells throughout the body by injection of this vector into the bloodstream from where it can access all tissues, including the brain. The goal of our study is to test this gene therapy approach in mouse models of TSC1 and TSC2 to serve as the preclinical studies needed to consider clinical trials in TSC patients.

Gene therapy using this strategy should reduce lesion size in tissues throughout the body. Initial targets for this therapy would be: (1) lymphangiomyomas in the lungs, which can be life-threatening and only partially responsive to drug treatment; (2) subependymal nodules in the brain ventricles, which can cause sudden death through blockage of the flow of cerebral spinal fluid; and (3) angiomyolipomas in the kidney, which can compromise function of this organ and clearance of toxic substances from the body. Delivery of the normal protein to cells lacking this protein in different tissues should reduce the size of lesions and prevent them from becoming cancerous. Although it would be hard to replace the protein in all affected cells, even correcting many of these cells should have therapeutic benefit. Gene therapy using the proposed vector has been evaluated in thousands of clinical trials following injection into the bloodstream or directly into affected tissues. Dose toxicity studies have been performed, and at doses that have proven beneficial, there is low-to-no adverse effects of the vector itself. In the case of TSC, we cannot be sure as yet whether overexpression of a normal version of the defective protein would be toxic, but believe it will not and will be able to assess this in mouse models. Since patients with TSC1 or TSC2 make normal tuberin or hamartin in most cells of the body, there should be no autoimmune reaction to the replacement protein expressed by the vector. Since we will have to condense the structure of tuberin to fit its coding sequence into the vector, there is a small possibility that this altered form will elicit an autoimmune response that could have toxic consequences, and again, although considered unlikely, this must be evaluated.

Dr. Elizabeth Thiele and I are currently presenting our data on gene replacement therapy for hamartin in TSC1 to biotechnology companies interested in gene therapy products. In order to cover the expense of generating clinical grade vector and carrying out the necessary studies for Food and Drug Administration approval of a Phase 1 clinical trial, it will be necessary to have a company partner. A current limitation to their interest is that we have only demonstrated benefit in mouse models for brain lesions and only for TSC1. The current proposal is addressing this limitation by expanding our mouse models to include lesions in other tissues, including kidney and lung, and replacement of tuberin for TSC2. Once a company is identified that will partner with us, we estimate it would take only 2 years to begin a clinical trial in TSC1 patients. It would take about 4 years, if our approach to delivery of tuberin works for a clinical trial in TSC2 patients. Based on clinical trials used to support use of drug therapy for TSC, benefit should be seen as early as 2 months after treatment through reduction in size of kidney lesions. However, for gene therapy trials, additional time would be needed, at least a year to follow patient outcome. Clinical trials normally go through three phases, which can in itself take 5 years or more before the product is available for clinical use.

In summary, our strategy for gene therapy has the advantages that therapy can be achieved from a single application, as compared to repeated treatment with drugs, and that AAV vectors have been found to have minimal to no toxicity in clinical trials for other neurologic conditions with long-term benefit. Although there are many additional issues to be addressed, our studies support the potential of gene therapy as a beneficial approach in TSC patients.