Dear ALD Community,
I hope that this report finds you and your family well despite this new world we live in. I would like to first thank you for your trust and for the amazing contributions you have made to help our adrenoleukodystrophy (ALD) research program. Not only did we receive financial donations, but we are delighted that our patients continue to be interested in participating in research activities and providing us their time, and entrusting us to serve as their healthcare providers.
With a dramatic year finally coming to an end, I’d like to take this opportunity to provide you with an update of our ALD research at the Moser Center for Leukodystrophies at Kennedy Krieger Institute.
Kennedy Krieger Institute's Response to the Pandemic:
The COVID-19 pandemic has had the most profound impact on everything we do as human beings, and unfortunately, will continue to affect all of us for several more months. Around the third week of February 2020, Kennedy Krieger Institute’s senior leadership put together a COVID-19 task force in anticipation of an upcoming surge and we started to project the impact of the pandemic on our patients and operations. On March 16 2020, the Governor of Maryland shut down public schools which resulted in an immediate impact on all of our activities, employees and patients. In response to this decision, Johns Hopkins University stopped all trainee activities and all research operations aside from critical research related to COVID-19. Like most hospitals, we incurred massive financial losses due to the cancelation of elective clinical appointments. Within 5 days, Kennedy Krieger was able to implement a telemedicine-based approach, and by the beginning of April, we had ramped up telehealth visits to over 5000 visits per week, with only 50-80 patients coming to the Institute. Meanwhile, we had to dramatically restrict access to our inpatient neurorehabilitation unit which houses very fragile children. While the virus has affected the health of many of our employees, and some have even lost family members, we have been able to keep our patients safe. During this time, interventional clinical trials have continued including the ones involving ALD patients. Importantly, I was thrilled yesterday to put my name in the waitlist to receive the COVID vaccine and hope that in the coming months, a large percentage of the world population will be vaccinated and we will be able to look beyond this pandemic so that we can continue our fight against ALD.
Despite the pandemic we were able to make significant progress over the last year in ALD research, and an effective therapy is becoming more and more of a tangible goal! Those of you who attended the ALD Connect annual conference last month will know that there continues to be multinational efforts, both from academic researchers and from industry partners, to develop therapies for the various forms of ALD.
As an example of this progress, a few weeks ago, one major industry-sponsored multinational randomized placebo controlled clinical trial in men with Adrenomyeloneuropathy (AMN) was completed. The Moser Center took part in this study and had provided the company with the natural history data needed to design the trial. The results of this new study are now being analyzed and we expect to soon find out whether the intervention was effective.
At least three other companies are gearing up to start clinical trials in AMN, and I am delighted to say that the Moser Center will continue to partner with these companies to again allow our patients to participate in these studies. Furthermore, the trial of ex vivo gene therapy in boys with cerebral ALD also continues and will soon come to completion. While not a trial site, the Moser Center is involved with several aspects of this trial.
There are several challenges in conducting successful clinical trials in ALD and other rare diseases. Firstly, the natural history of the disease is not well known and variable rates of disease progression make the unbiased assessment of therapies difficult. Secondly, there is a need to identify markers that can predict disease progression in advance to allow stratification of the right set of research participants into trials. In addition, the lack of ALD expertise in many geographical areas hampers the enrollment of a sufficient number of research participants into trials. For this reason, here at Kennedy Krieger Institute, we have been focusing on: 1) developing remote assessment protocols using wearable technology, and 2) identifying biomarkers that predict disease progression.
Harnessing Wearable Technology to Remotely Assess Patients in Clinical Trials:
In 2017, in partnership with Dr. Amy Bastian, Chief Science Officer at Kennedy Krieger Institute, we began a new research project utilizing a wearable technology platform that had been used in Parkinson’s Disease as a tool to remotely assess patients’ balance, walking speed, and other gait measures. An outstanding young physician scientist in our group, Dr. Amena Smith Fine, has quickly gained expertise in this methodology and has deployed this wearable platform in a series of patients with childhood onset leukodystrophies. We collaborate with a group of computer and biomedical engineering specialists utilizing Artificial Intelligence (AI) techniques to analyze such data.
Last year we were able to secure a consortium grant funded by the National Institutes of Health in collaboration with Dr. Florian Eichler at Harvard University and Dr. Adeline Vanderver at Children’s Hospital in Philadelphia, which provides us funding to conduct a longitudinal study in men and women with AMN using wearable technology and AI tools and to remotely assess their gait dysfunction. We are currently in the process of enrolling the first set of patients into this study and hope to enroll at least 20-30 patients within the next year. Importantly, this data will be very useful for future clinical trials which could be conducted at patients’ homes, facilitating access to these trials.
Identifying Predictors of Disease Progression:
A major challenge in ALD research remains our inability to predict, for an individual who has the ALD genetic anomaly, when the disease will start and what form of ALD they will develop. While newborn screening is spreading across the United States, we still have no way to determine the age at which positively screened newborn babies will present with neurological symptoms. In addition, we do not know how fast the disease will progress once symptoms start.
In collaboration with Dr. Jaspreet Singh at Henry Ford Medical System, we have conducted a study measuring thousands of blood metabolites and other small molecules referred to as microRNAs, and we have found a series of markers that appear to strongly correlate with the severity of neurological impairment in AMN patients. In addition, we have found several markers that show strong differences between different forms of ALD (cerebral ALD, versus AMN). We are now in need of funding to conduct a prospective study to determine whether these blood biomarkers can in fact predict the severity of the disease in the future. This study would ideally be done to complement the studies using wearable technology. Together with Dr. Singh, we have applied to the NIH for several grants in the hopes of receive funding to conduct this study.
In addition, over the last two years we have established a collaboration with Dr. Mathias Unberath at the Johns Hopkins Malone Center for Computer Engineering in Healthcare who, together with our talented physician scientist Dr. Bela Turk, has developed a series of AI applications for automated analysis of large data sets including plasma biomarkers, clinical measures and MRIs. Together, this has become the “Moser Center Neural Network”, an AI tool that integrates multiple types of data to develop prediction tools.
Using Animal Models and Cell Cultures to Understand Disease Mechanism:
It remains unknown why males with ALD can present with either the childhood-onset or adult- onset forms of the disease. Under the leadership of Dr. Christina Nemeth Mertz in our lab we are conducting large scale gene expression studies in ALD mice that are exposed to brain injury, and using this to try to identify the underlying factors that result in the different forms of ALD. In addition, we have developed ‘minibrains’ in the dish from patient derived stem cells and are currently investigating these specimens as a potential testbed for future therapies. Most of this work has been relying heavily on funds from donations.
None of this could have been achieved without teamwork. I am blessed to work with a fantastic team of clinicians, nurses, researchers and trainees who are dedicated to our work. At the Moser Center, we take an interdisciplinary approach, and collaborate not just within the center, but with other specialists and scientists across the world to ensure that every one of our patients receives the best possible care, and in the hope that we find a cure against ALD.
Thank you for continuing to believe in our mission. The ALD community is our family, and there is nothing that matters more to us than eradicating leukodsytrophies. We’d be honored if you would consider making a contribution to the Moser Center, and we wish you a happy holiday season and all the best for 2021.
Ali Fatemi, MD, MBA
Director, Moser Center for Leukodystrophies
Chief Medical Officer, Kennedy Krieger Institute