Autosomal Dominant Leukodystrophy (ADLD) Research
Title: LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
Principal investigator: Adeline Vanderver, MD
Children’s Hospital of Philadelphia
Leukodystrophies are a group of approximately 30 genetic diseases that primarily affect the brain’s white matter, a complex structure composed of axons sheathed in myelin, a glial cell-derived lipid-rich membrane. Leukodystrophies are frequently characterized by early onset, spasticity, developmental delay, and are degenerative in nature. As a whole, leukodystrophies are relatively common (approximately 1 in 7000 births or almost twice as prevalent as Prader-Willi Syndrome, which has been far more extensively studied) with high associated healthcare costs. However, more than half of the suspected leukodystrophies do not have a definitive diagnosis and are generally classified as “leukodystrophies of unknown etiology.” Moreover, even when a diagnosis is achieved, the diagnostic process lasts an average of eight years. It results in test expenses in excess of $8,000 on average per patient, including most patients who never achieve a diagnosis at all. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients. The diagnostic workup begins with cranial Magnetic Resonance Imaging (MRI) followed by sequential targeted genetic testing. However, next-generation sequencing technologies (NGS) promise rapid and more cost-effective approaches.
Despite significant advances in diagnostic efficacy, there are still substantial issues concerning the implementation of NGS in clinical settings. First, sample cohorts demonstrating diagnostic efficacy are generally small, retrospective, and susceptible to ascertainment bias, ultimately rendering them poor candidates for utility analyses (to determine how efficient a test is at producing a diagnosis). Second, historic sample cohorts have not been examined prospectively for information about the impact on clinical management (whether the test results in different clinical monitoring, a change in medications, or alternate clinical interventions).
To address these issues, the study team investigated patients with suspected leukodystrophies, or other genetic disorders affecting the white matter of the brain, at the time of initial confirmation of MRI abnormalities. A prospective collection of patients randomly received on a “first come, first served” basis from a network of expert clinical sites was developed. Subjects were randomized to receive early (1 month) or late (6 months) WGS, with SoC clinical analyses conducted alongside WGS testing. An interim analysis performed in May 2018 assessed these study outcomes for a cohort of thirty-four (34) enrolled subjects. Two of these subjects were resolved before complete enrollment and were retained as controls. Nine subjects were stratified to the Immediate Arm, of which 5 (55.6%) were resolved by WGS and 4 (44.4%) were persistently unresolved. Of the 23 subjects randomized to the Delayed Arm, 14 (60.9%) were resolved by WGS and 5 (21.7%) by SoC, while the remaining 4 (17.4%) remained undiagnosed. The diagnostic efficacy of WGS in both arms was significant relative to SoC (p<0.005). The diagnosis time was significantly shorter in the immediate WGS group (p<0.05). The overall diagnostic efficacy of the combination of WGS and SoC approaches was 26/34 (76.5%; 95% CI = 58.8% to 89.3%) over <4 months, greater than historical norms of <50% over more than five years.
The study now seeks to determine whether WGS results in changes to clinical management in subjects affected by undiagnosed genetic disorders of the white matter of the brain relative to standard diagnostic approaches. We anticipate that WGS will produce measurable downstream changes in clinical management, as defined by disease-specific screening for complications or the implementation of disease-specific therapeutic approaches.
Title: UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells (DUOC-01)
Principal investigator: Joanne Kurtzberg, MD
Duke University Medical Center
Inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, primarily involving a single gene mutation resulting in an enzyme defect. In the majority of cases, the enzyme defect leads to the accumulation of substrates that are toxic and/or interfere with normal cellular function. Often, patients may appear normal at birth but begin to exhibit disease manifestations during infancy, frequently including progressive neurological deterioration due to absent or abnormal brain myelination. The ultimate result is death in later infancy or childhood.
Currently, the only effective therapy to halt the neurologic progression of the disease is allogeneic hematopoietic stem cell transplantation (HSCT), which serves as a source of permanent cellular ERT.3 However, one barrier to the success of this therapy is delayed engraftment of donor cells in the CNS when administered through the intravenous route, which is associated with ongoing disease progression over 2-4 months before stabilization. The engraftment of donor cells in a patient with an IMD provides a constant source of enzyme replacement, thereby slowing or halting the progression of the disease.
This study will evaluate the safety of a potential new treatment for patients with certain IMDs known to benefit from HSCT using allogeneic UCB donor cells. The new intervention, intrathecal administration of UCB-derived oligodendrocyte-like cells (DUOC-01) will serve as an adjunctive therapy to a standard UCB transplant. This therapy aims to accelerate the delivery of donor cells to the CNS, thereby bridging the gap between systemic transplant and engraftment of cells in the CNS and preventing disease progression. The DUOC-01 cells and cells used for HSCT will be derived from the same UCB donor unit.
Title: Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)
Principal investigator: Paul Szabolcs, MD
UPMC Children’s Hospital of Pittsburgh
For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies), a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. However, HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage resulting from the underlying disease may remain present after the HSCT.
For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the primary intent of the transplant is to slow down, or stop, the progress of the disease. In a select few cases/diseases, the presence of healthy bone marrow-derived cells may even prevent progression and prevent neurological decline.
In this research study, instead of using the standard myeloablative conditioning, the study uses RIC, in which significantly lower doses of chemotherapy are administered. The lower doses may not eradicate every stem cell in the patient’s bone marrow. However, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to the successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress the patients’ surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe, and late toxic effects should also be reduced.
This study aims to collect data from the patients undergoing reduced-intensity conditioning before HSCT and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with a better survival rate, less organ toxicity, and improved quality of life following the RIC compared to the myeloablative regimen.