Major Lectureships and Seminars
- Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months. New York State Krabbe Consortium Meeting. New York, NY. November 2018.
- The importance of natural history studies – DDX3X. 4th Annual DDX3X Medical and Family Conference. Philadelphia, PA. October 2018.
- Patient and caregiver experience with pantothenate kinase-associated neurodegeneration. Child Neurology Society Meeting. October 2018.
- Keynote Speaker, The challenges of racing to treat neurodevelopmental disorders. A-BOM Meeting. UNC Chapel Hill, NC. August 2018.
- Sanfilippo, LSD Manifestations in the CNS. MPS Symposium. San Diego, CA. August 2018.
- Natural history of Metachromatic leukodystrophy. MLD Family Conference. Philadelphia, PA. July 2018.
- Neurocognitive Evaluations in Lysosomal Storage Disorders. ASGCT Symposium. Chicago, IL. May 2018.
- Early diagnosis and improved outcomes using automated neuroimaging software and reduced toxicity conditioning regimens for the treatment of leukodystrophies. ALD Standard of Care Meeting. Brooklyn, NY. January 2018.
Professional Affiliations/Society Memberships
- American Society of Gene and Cell Therapy
- Adrenoleukodystrophy Advisory Board, Bluebird Bio
- Sanfilippo Syndrome Advisory Board, BioMarin
- MPS II Advisory Board, Regenxbio
- Zellweger Spectrum Disorders Advisory Board, Retrophin
- Advisory Board, Abeona
- Shire Human Genetics
- Global Leukodystrophy Association
- Newborn Screening Translational Network Workgroup, ACMG, supported by the National Institute of Child Health and Development
- Medical Advisory Board, Jacob’s Cure
- New York State Krabbe Newborn Screening Consortium
- Medical and Scientific Advisory Board, MLD Foundation
- Krabbe Translational Research Network
Education & Training
- MD: Escuela Colombia De Medicina Santefe De Bogata, Colombia
- MS: Columbia University College of Physicians and Surgeons New York, NY
- Residency: Cornell Medical Center Hospitals New York, NY
- Fellowship: Cornell Medical Center Hospitals New York, NY
Dr. Maria Escolar’s research takes a multidisciplinary approach focused on the interactions of genes, brain, and behavior and their influences on aberrant development in rare neurodegenerative diseases. Dr. Escolar is an expert in leukodystrophies, such as Krabbe disease, metachromatic leukodystrophy (MLD), and adrenoleukodystrophy (ALD), as well as other metabolic conditions that can affect the brain, such as Sanfilippo syndrome, Hurler’s syndrome, and Hunter’s syndrome, among others.
Natural History of Krabbe Disease. Krabbe disease, also known as globoid cell leukodystrophy, is a rare autosomal recessive metabolic disorder characterized by the deficiency of galactocerebrosidase, a lysosomal enzyme responsible for the degradation of psychosine to galactose and sphingosine. The subsequent accumulation of psychosine destroys oligodendrocytes and Schwann cells, causing the formation of multi-nucleated globoid cells, severe demyelination, axonopathy, and neuronal death. The degradation of the central and peripheral nervous systems clinically manifests as progressive neurodegeneration, spasticity, irritability, blindness, deafness, seizures, and premature death. The incidence of Krabbe disease has been estimated as 1 in 100,000 live births. The disease is divided into four subgroups based on age at symptom onset: early infantile (birth to 5 months), late infantile (6–36 months), juvenile (3–17 years), and adult (> 18 years).
As a leading center in the study and treatment of Krabbe disease, the NDRD team has evaluated more than 180 patients, providing the largest single-center database on Krabbe disease in the world. Because of the large and comprehensive database, Dr. Escolar has been able to advance research on the different phenotypes. With 101 early- infantile patients and 41 late-infantile patients, Dr. Escolar has designed natural history studies to evaluate variability in progression. In Dr. Escolar’s natural history design, children are evaluated prospectively following a protocol of standardized multidisciplinary testing. Evaluations are completed by a multidisciplinary team of specialists, including neurodevelopmental pediatricians, neuroradiologists, ophthalmologists, speech pathologists, audiologists, physical therapists, genetic counselors, and psychometricians.
Overall, the data collected help establish the initial symptoms and characteristics of disease progression, which is beneficial in staging the disease. Resolution of early symptoms can be used for monitoring disease progression and assessing the efficacy of therapeutic interventions. Further work is necessary to understand the correlations among symptoms, function, and genetic mutations. A better understanding of the presenting symptoms of Krabbe disease will increase awareness among pediatricians and result in earlier diagnostic referrals and recruitment for future clinical trials. Such knowledge will become increasingly important as methodological and legislative advances in newborn screening practices continue. Ultimately, natural history data will enable researchers to establish the rate and severity of disease progression, allowing clinicians to make better decisions regarding the management and treatment of patients diagnosed via newborn screening.
Psychosine, a Marker of Krabbe Phenotype and Treatment Effect. Although the phenotypic spectrum associated with this condition is broad, the most common form, known as early- infantile Krabbe disease, results in rapid neurodegeneration and death within the first few years of life. Since the only treatment for this condition, hematopoietic stem cell transplantation (HSCT), is most effective if performed prior to the onset of neurological deterioration, it is essential that affected patients be diagnosed during the presymptomatic or minimally symptomatic period. Biomarkers are urgently needed to aid in the prediction of phenotype and assessment of clinical course in patients who are diagnosed with or determined to be at risk for Krabbe disease. Two small prior studies have found evidence that the concentration of psychosine, a substrate of the galactocerebrosidase enzyme, is elevated in patients with early-infantile Krabbe disease. However, given that the prior studies were limited to cross-sectional measurements in a small number of patients, additional data are needed to assess the value of dried blood spot (DBS) psychosine as a potential biomarker for Krabbe disease.
In July 2017, Dr. Escolar reported the findings of the largest study of DBS psychosine concentrations in patients with Krabbe disease to date. The team was the first to longitudinally assess DBS psychosine concentrations in a phenotypically diverse cohort of patients with early-infantile, late-infantile, and juvenile-onset Krabbe disease, along with carriers and at-risk patients who screened positive for Krabbe disease at birth but remain asymptomatic. Substantially elevated DBS psychosine during the newborn period has 100% specificity as a biomarker for infantile-onset Krabbe disease. The findings suggest that measuring psychosine as a second-tier newborn screening test could aid in phenotypic prediction and help clinicians to determine which patients require urgent treatment with HSCT. Future work is aimed toward examining the relationship between psychosine increase and disease progression in later-onset patients and the implications of psychosine concentration changes over time.
Developmental Outcomes of Cord Blood Transplantation for Krabbe Disease: A 15-Year Study. Currently, Krabbe disease has no cure, but hematopoietic stem cell transplantation (HSCT) has been shown to significantly improve neurological outcomes in asymptomatic neonates. However, when transplantation is performed in symptomatic patients with early-infantile disease, the neurologic insult remains severe. The purpose of this prospective study, which was accepted for publication in Neurology in August 2017, was to summarize long-term neurodevelopmental outcomes of 18 children with early-infantile Krabbe disease who were transplanted in the first 7 weeks of life. Long-term outcomes of transplanted patients were assessed with a standardized protocol. Despite failing to cure Krabbe disease, HSCT performed before the onset of severe symptoms delayed disease progression and improved length and quality of life. Children who survived the peritransplant period functioned at a much higher level than untreated patients. Gross motor function responded less well to treatment, whereas fine motor skills were generally preserved. Cognition was normal or developed at a slightly slower rate than that of typical children. The clinically and statistically significant associations between age at transplantation and expressive language and gross motor function highlight the importance of transplantation as soon as possible for children with early-infantile disease, ideally before 2 weeks of age.
Improvements in Brain Development Following HSCT in Krabbe Disease. Krabbe disease causes severe demyelination of the brain with rapidly progressing atrophy of certain regions. HSCT is the only treatment available that can halt disease progression. In this study, the NDRD team investigated the development of cerebral myelination by magnetic resonance imaging (MRI) and propose a more sensitive and objective tool to assess the effects of this treatment. The team also compared MRI data from patients who underwent HSCT against natural history. Diffusion tensor imaging (DTI), which utilizes fractional anisotropy to measure the water diffusion property of the white matter and reflects the direction of the axonal microstructure, was used to assess the white matter integrity of the brain. Combined with Dr. Escolar’s neuroimaging protocol and algorithm, the methods allow for precise quantification of myelin content. A total of 55 patients with early-infantile Krabbe were analyzed; 14 underwent transplantation and 31 had natural disease progression. Patients treated with HSCT mostly followed the normal developmental trajectory of the corticospinal tract, albeit in the lower part of the normal range. Patients who were not treated with HSCT started with lower-than-normal fractional anisotropy, and the measure decreased significantly within two years after an initial increase. The fractional anisotropy values are consistent with the motor function as measured by behavioral testing. Diffusion-based brain MRI quantitates abnormalities in white matter integrity in patients with early-infantile Krabbe disease. Patients who are treated with HSCT early in life retain corticospinal tract integrity and follow a normal trajectory over time. More broadly, the findings support using diffusion tensor imaging as a tool to measure white matter integrity and effects of treatment in persons with neurodegenerative diseases.
Treatment of Krabbe Disease with Intravenous Adeno-Associated Virus Gene Therapy. Treatment with HSCT can extend life and preserve cognitive function in presymptomatic patients with early-infantile Krabbe disease and in presymptomatic/minimally symptomatic patients with the late-infantile form of the disease. However, all treated children experience some degree of motor disability post-HSCT due to a combination of peripheral nerve disease and early, irreversible damage of the corticospinal tracts. Furthermore, HSCT offers no significant benefit once a patient is already symptomatic because of the extensive early damage to the motor tracts. Therefore, no effective treatments are available once a child manifests signs or symptoms of Krabbe disease. Intravenous gene transfer has been shown to correct myelination of both central and peripheral nervous systems in mice, addressing the critical problem that HSCT is not able to correct—progressive deterioration of the peripheral nerves. In mice, intravenous gene therapy administered shortly after HSCT rapidly improves myelination in both brain and peripheral nerves while the immune system reconstitutes after myeloablative conditioning. In this way, adding gene therapy may shorten the interval between diagnosis and delivery of normal galactocerebrosidase enzyme to oligodendrocytes and Schwann cells, potentially extending the benefits of treatment to patients who have begun to show symptoms.
There is renewed interest in gene therapy, as the development of new viral vectors has reduced the risk of immunogenicity and insertional mutagenesis. Results of recent clinical trials evaluating gene therapy for genetic diseases such as ALD and MLD are highly encouraging. Recent advances in gene delivery technologies and the team’s newly patented treatment combining gene therapy with reduced-conditioning HSCT may hold the key to effective treatment for more infants and children affected by Krabbe disease. If successful, the proposed clinical trial may transform the standard of care for patients with Krabbe disease. Currently, the project is in the preclinical stages: the toxicology studies. Once those studies are completed, the team intends to move into a phase I/II clinical trial, which will test for safety and explore efficacy in humans.
Krabbe Translational Research Network. Dr. Escolar began holding the annual Krabbe Translation Research Network (KTRN) meeting in 2010 while at the University of North Carolina. The KTRN is a consortium of scientists and clinicians who are dedicated to helping children with Krabbe disease live longer and healthier lives. The KTRN brings together the complementary knowledge and skills of investigators who are working in different disciplines at different institutions; it aims to accelerate the development of research findings into new treatments. KTRN members share data and resources to identify promising therapeutic approaches for further development. Specific goals of this year’s meeting will include addressing the challenges of gene therapy and effective designs for future trials, discussing the use of gene therapy in patients who were previously transplanted, and considering the treatment of peripheral nerve disease.
Natural History of MLD. MLD is an inherited lysosomal storage disease caused by deficient activity of arylsulfatase A, an enzyme involved in the degradation of 3’-O-sulphogalactosylceramide, otherwise known as sulfatide. Sulfatide exists as a membrane-bound sphingolipid abundant in the myelin sheath and predominantly found in oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. In MLD, the gradual accumulation of undegraded sulfatide in these myelin-producing cells results in progressive demyelination and neurodegeneration in both the central nervous system and peripheral nervous system. The disease is fatal, with a variable clinical course, and it is typically classified into subtypes based on age of onset. The limitations of previous cohort studies inspired the team to carry out a larger, more comprehensive (prospective and retrospective) study of the onset, prevalence, and severity of clinical manifestations of MLD, enabling physicians to recognize early symptom onset and to select patients likely to benefit from current and future therapies. The data will be used to design clinical trials and to assess treatment outcomes. Since all evaluations were conducted at a single site with a standardized protocol, the data are the most reliable to date. They also favor patients with early onset, the time of greatest therapeutic opportunity. The substantially larger cohort—totaling 134 patients—enabled arraying the population on a continuous spectrum as opposed to discrete subtypes. The approach allows physicians to conceive of the disease as a diverse set of symptoms and varying forms of clinical presentation, instead of distinct, nonoverlapping phenotypes. In sum, the prospective, longitudinal study provides an improved understanding regarding the clinical course of the insidious disease. The findings will lead to improved clinical outcomes by facilitating earlier diagnoses and assisting in the treatment and management of MLD. Additionally, they will provide a baseline for investigators designing clinical trials for novel therapies.
NDRD Brain and Tissue Bank. This biorepository is housed in Rangos Research Center, and post-mortem specimens are housed at the Alzheimer’s Brain Bank at the University of Pittsburgh. It currently houses more than 1,000 specimens collected since 2010. The project has been funded by grants awarded by the Legacy of Angels Foundation and a donation from the Believing for Bryleigh Foundation and Partners for Krabbe Research. The tissue bank provides a plethora of research opportunities for multiple collaborations, as most specimens are connected to clinical data in the NDRD database. Dr. Escolar works closely with Julia Kofler to draw connections among histological, pathological, and clinical findings.
Clinical Trials. In addition to coordinating internal research at the NDRD, Dr. Escolar continues to be involved as principal investigator in several industry-sponsored projects. Current projects include a phase II/III trial investigating a treatment for pantothenate kinase-associated neurodegeneration, a retrospective cross-sectional study to evaluate the neurodevelopmental status of patients with severe MPS type II, and a phase I/II trial investigating the safety and efficacy of gene therapy in patients with severe MPS type II.