2024
1 Million Dollar Grant Awarded to Gene Therapy
The Gene Therapy team at Boston Children’s Hospital was awarded approximately one million dollars for the next three years to continued work on Gene Therapy. Drs. Rotenberg and Lee will work with Guangping Gao, PhD, leveraging his expertise with the adeno-associated virus (AAV), a versatile viral vector technology that can be engineered for very specific functionality in gene therapy applications.
Second fold, Dr. Afshar-Saber’s will test Gene Therapy on an vitro model of SSADHD using patients iPSC derived neurons to show the efficacy of gene therapy in SSADHD patients similar to the test on the mouse model.
Prevalence Study and Newborn Screening Assay
Dr. Sarah Elsea continued her work to capture and publish the worldwide prevalence of SSADH Deficiency. Additionally, she has developed and is testing a newborn screening assay panel for 10 biomarkers covering nearly 22 disorders including SSADH Deficiency using a dried blood spot.
2023
Grand Rounds at Boston Children's Hospital
SSADH Deficiency was the topic for the Boston Children’s Hospital Metabolism Grand Rounds. Phillip L. Pearl, M.D. shared the results of the Natural History Study, Including the review of the clinical, imaging, and neurophysiologic outcomes of the study. He also correlated longitudinal changes of the course of the disorder with GABA activity and other biomarkers. Dr. Pearl wrapped up by outlining the emerging therapeutic strategies for SSADH deficiency.
Click here to view the Grand Rounds Recording
Gene Replacement Therapy Proof of Concept grant for SSADH Deficiency
Dr. Henry Lee was granted $49,000 from the SSADH Association for a nine month period to evaluate the restoration parameters on the SSADH Inducible Mouse Model. The goal of this grant is to identify the three key topics of: Rate of Restoration, Age of Restoration and Cell Specificity of Restoration Targets. This proof of concept work can then be used to secure further funding from alternative sources.
Continued work on the in vitro model for drug screening
Mustafa Sahin MD, PhD and Wardiya Afshar-Saber, PhD from Boston Children’s Hospital / Harvard Medical School have successfully established a platform for SSADH Deficient drug screening using induced pluripotent stem cells derived neurons. Thus, allowing for a robust in vitro model for excitatory and inhibitory work.
Prevalence Study and Novel Newborn Screening Programs
Sarah Elsea, Ph.D., FACMG Professor, Dept. of Molecular and Human Genetics and Senior Director Biochemical Genetics at Baylor College of Medicine published her work documenting the genomic variants for SSADH and concluded that there are currently 98 reported variants, which indicates 1:460,000. She is now shifting her focus to establish the best possible approach for diagnosing SSADH Deficiency from a newborn screening card. This is the step before launching a newborn screening pilot program for SSADH deficiency on a state wide level.
2022
Developing an Inducible Mouse Model for Gene Replacement Therapy in Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD)
This grant was awarded to Drs. Henry Lee and Alex Rotenberg at Boston Children's Hospital for a total of $221,250 for a two year period ending 12/31/2023 from the National Institutes of Neurological Disorders and Stroke (NINDS).
The goal of this grant is to further test SSADH-restoring strategies such as enzyme replacement therapy and gene therapy as a potential cure for this debilitating disorder, but the impact of haphazard SSADH restoration in a pre-existing condition of reduced GABA receptors might evoke seizures and lead to further brain damage.
Drs. Lee and Rotenberg aims are to develop an inducible mouse model which allows `on-demand' SSADH expression in a controllable, cell-specific fashion, such that key parameters of safe SSADH restoration will be determined in great details, advancing the preclinical development of novel treatment and de-risk gene therapy and enzyme replacement therapy for SSADHD patients.
Click here to view the grant award notice on the National Institutes of Health website.
2021
The SSADH Association committed $50,000 for a fellowship program with Dr. Jens Andersen at the University of Copenhagen, Denmark to evaluate the “Molecular Pathological Mechanisms of CaMK2a in SSADH Deficiency” under the guidance of Dr. Petrine Wellendorph, an international leader in the neuroscience community related to GHB/GABA research. The funds will also be used to support a part-time animal tech.
Dr. Andersen’s fellowship with begin January 1st 2022 an run for six months at which time he will be supported by a five year $1.5 million grant secured by Dr. Wellendorph.
Dr. Gibson is supplying the group in Denmark with a SSADH mouse to establish their SSADH mouse model colony to begin their important research.
The SSADH Association awarded $55,000 to Henry Lee, Ph.D., Alexander Rotenberg, Ph.D., MD, and Phil Pearl, MD from Boston Children’s Hospital / Harvard Medical School to continue evaluating the potential for Enzyme Replacement Therapy for SSADH patients.
The grant period will begin July 1, 2021 and run for six months to evaluate the optimal enzyme restoration parameters in the SSADH inducible mouse model. The goal of this grant is to evaluate three critical aims for enzyme replacement therapy (rate, age and location) using the mouse model. We are hopeful that the additional six months with help to position this research for further funding by federal and/or private sectors. This project is an extension from the initial project to create the inducible mouse model.
$100,000 was awarded to Drs. Gibson and Roullet at Washington State University to extend the initial funding of the SSADH Biorepository for the period of 10/01/21 to 05/31/23. This end date coincides with the current end date of the Natural History Study.
The Biorepository is storing all the samples secured from the Natural History Study regardless of the patient sites.
The samples have been used extensively to search for novel biomarkers of SSADH deficiency markers that could potentially be used for newborn screening as well as developing novel treatment strategies.
European colleagues are investigating novel biomarkers in physiological fluids from SSADH patients.
The WSU team, in conjunction with their colleagues at the North Carolina State University have begun to explore circadian rhythms and associated clock genes using blood samples.
Dr. Claudio Cinquemani, head of the German SSADHD PAG (parent advocacy group) is working on a gut microbiome project of SSADH-deficient patients with the aim to understand the deficiency better and possibly derive therapies from the knowledge gained.
The initial grant to establish and maintain the Biorepository from the SSADH Association was for $305,000 covering the period from 10/1/16 to 09/30/21.
$11,000 was awarded to JEX Services to maintain a Backup Mice Colony. The backup colony is insurance should animal contamination occur within the primary colony at Washington State University that there will not be a lapse in research due to the lack of SSADH mice.
Because of the COVID pandemic and the mandatory shut down of research facilities across the United States both of the following grants have been extended to 6/30/2021 and 3/31/2022 respectively:
Developing an Inducible SSADH Deficient Mouse Model for Enzyme Replacement Therapy
Developing SSADH Deficient GABA’ergic Cells
2020
$100,000 was awarded to Phillip Pearl, MD & Alexander Rotenberg MD, PhD at Boston Children’s Hospital in May of 2020, to develop a SSADH mouse model for Enzyme Replacement Therapy. Their goal will be to create an inducible animal, which means it will allow them to turn off the SSADH enzyme at birth, during adolescence, and in adulthood. The results for this project will be imperative for preclinical studies leading to the possibility of additional NIH funding of enzyme replacement therapy for SSADH patients.
$10,000 was awarded to JEX Services to maintain a Backup Mice Colony. The backup colony is insurance should animal contamination occur within the primary colony at Washington State University that there will not be a lapse in research due to the lack of SSADH mice.
Because of COVID-19 this year the mice colony at Washington State University had to be euthanized as the staff was ordered into isolation. Thankfully the backup mice colony will allow the team to quickly regroup once the university reopens.
2019
Funds were awarded to Sarah H. Elsea, PhD. to determine the prevalence of SSADH Deficiency by estimating the ALDH5A variants both within the US and world wide.
In support of the Natural History Study and the SSADH Biorepository $25,000 was approved to fund the travel expenses of families living outside of the United States to participate in this study at Boston Children's Hospital.
Additionally, $37,000 was committed to provide an extra $1,500 beyond the travel funds within the grant from the Natural History Study for US families traveling to Boston Children's Hospital.
$10,000 was awarded to JEX Services to establish a Backup Mice Colony to ensure the availability of SSADH Mice should something happen to the existing colony at Washington State University, preventing any lapse in research due to the lack of SSADH mice.
2018
$125,000 was awarded to Phillip Pearl, MD & Mustafa Sahin MD, PhD at Boston Children’s Hospital and Harvard Medical School. Our award was matched by an anonymous $175,000 donation on behalf of the Boston Children’s Hospital Trust.
This project will be a continuation of our initial funding from 2015 to create SSADH stem cells and heterozygous controlled GABA’ergic iPSC lines. The goal of this phase will be to use the patient iPSC neurons to screen for novel therapeutic approaches to treatments.
$12,000 was awarded to Ritva Tikkanen, MD, PhD from Justus-Liebig Universität Gießen, Germany to create molecular consequences of SSADH mutations allowing for mutation specific therapies. Dr. Tikkanen will be using the SSADH stem cell lines created at Boston Children’s Hospital.
$10,000 was awarded to JEX Services to establish a Backup Mice Colony to ensure the availability of SSADH Mice should something happen to the existing colony at Washington State University, preventing any lapse in research due to the lack of SSADH mice.
2017
Up to $305,616 was awarded to K. Michael Gibson, PhD, FACMG at Washington State University for the SSADH Biorepository project which aims at creating a biobank where biospecimens and matching clinical data are collected longitudinally from all interested parties: patients, siblings and family members and unaffected, age-matched control individuals.
The Biorepository will be created over the next five years with the following team: Drs. Gibson and Roullet, (WSU), Dr. Pearl (BCH), Dr. Opladen (iNTD, Heidelberg, Germany) and the SSADH Association.
The Boston Children’s Hospital team of Phil Pearl, MD & Robin Kleiman, PhD were provided $100,000 to develop an in vitro disease model of SSADH from patient iPSC lines differentiated into GABAergic neurons that will support phenotypic drug screening. They have successfully created three patient cell lines and three heterozygous controls, one with the CRISP-R
correction for state of the art testing by allowing for an isogenic control which allows researchers to control for the effects of other genes.
The next stage, which has already started, is to identify the best clones for phenotyping of the cells. The plan is to start with cellular electrophysiology and assays of the cellular characteristics, including organelle quantification, RNA sequencing and microRNA research.
$10,000 was awarded to JEX Services to maintain a Backup Mice Colony to ensure the availability of SSADH Mice should something happen to the existing colony at Washington State University, preventing any lapse in research due to the lack of SSADHD mice.
The SSADH Association was working with Dr. Gibson and Alice McConnell to get an ICD-10 code assigned to SSADH by the Centers for Disease Control (CDC) in the United States. This will allow medical professionals to code a doctor visit for SSADH.
We believe because the phenotype of SSADH patients is very broad, a unique ICD-10 code would help physicians identify patients and work together more effectively on SSADH issues.
2016
$100,000 was awarded to K. Michael Gibson, PhD, FACMG at Washington State University to garner efficacy data over a two year period, in the SSADH animal model to form the framework for the Investigational New Drug Application with the NIH for the use of compounds NCS-382 (GHB Antagonist) and HOCPCA.
This grant led to the success of a Small Business Technology Transfer (STTR) award from the National Institutes of Health (NIH) allowing for a Phase I Toxicology Study on NCS-382. The goal is to complete this study by the fall of 2017. Pending results, we will then apply for a Phase II study potentially moving NCS-382 into a NIH clinical trial.
$125,000 was awarded to Phil Pearl, MD & Robin Kleiman, PhD, to fund a one year research grant in conjunction with Boston Children’s Hospital and Harvard University. The objective of this project is to develop an in vitro disease model of SSADH from patient iPSC lines differentiated into GABAergic neurons that will support phenotypic drug screening.
$10,000 was committed to kick off a Natural History Study with the US medical team of Phil Pearl, MD, (Boston Children's Hospital), Jean-Baptiste Roullet, PhD, and Mike Gibson, PhD, FACMG, (both from WSU), together with Evangeline Wassmer, PhD (UK), Thomas Opladen, MD, (Germany) and Garcia-Cazorla, PhD, (Spain) who will work with the SSADH Association on a grant proposal to support a multi-year (5+) and multi-site natural history study of SSADH patients.
2015
$158,950 was awarded to the University of California, San Diego to determine if the induction of autophagy by rapamycin would remove surplus organelles, thus reducing oxidative stress and restoring cellular homeostasis which may lead to potential treatments for SSADH. Evaluation of autophagy in SSADH is being done to measure compounds in blood that provide evidence for disruption of the process called autophagy in patients. Autophagy is a process known to occur in microbes, whereby the body can regenerate nutrients from cells that have died or when the body is in need of energy during starvation.
$100,000 was awarded to K. Michael Gibson, PhD, FACMG at Washington State University to garner efficacy data in the SSADH animal model to form the framework for the Investigational New Drug Application with the NIH for the use of compounds NCS-382 and HOCPCA.
$5,000 was awarded to Kestutis G. Bendinskas, PhD at SUNY-Oswego to develop an easy to use field colorimetric assay screen to detect the biomarker for SSADH gamma hydroxybutyric acid (GHB), in either urine or saliva to screen candidates.
Preliminary discussions between the SSADH Association and Aldeyra Therapeutics have taken place to fund some additional research projects to further the understanding of a new medication that has showed some promising results to date in preliminary studies.
2014
$45,000 was awarded to the NIH for the Phase 2 Clinical Trial of SGS-742 Therapy in SSADH Patients. The money will be used to synthesize and encapsulate the SGS-742 compound for the Phase 2 Trial.
Evaluation of Metabolites in SSADH Urine is being studies by Kara Vogel, PhD. at Washington State University to explore the possibilities for SSADH patients.
Investigation of the immunological response in SSADH cells by Karen Newell-Rogers, PhD at
Texas A & M to understand the alterations in metabolism and immunity using the SSADH mouse model.
2013
SSADH Association awards a $79,500 Research Grant to Ronak Lakhani, PhD
Dr. Ronak Lakhani at the University of California, San Diego, will continue his 2013 SSADH research through 2014. Dr. Lakhani will determine if the induction of autophagy by Rapamycin would remove surplus organelles, thus reducing oxidative stress and restoring cellular homeostasis which may lead to potential treatments for SSADH.
SSADH Association awards a $79,450 Fellowship Grant to Ronak Lakhani, PhD
Dr. Ronak Lakhani is a Post-Doctoral Fellow at the University of California, San Diego. In early 2013, Dr. Lakhani submitted an application for the SSADH Association to fund a project that may lead towards an eventual clinical trial to treat SSADH.