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.
As of 10/2/2020 we are waiting for the NIH to publish the finding from the Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. This is a note from the Principal Investigator:
The first journal we sent it to did not accept it, so we are in the process of submitting to another where we hope to have better luck. Unfortunately each go-round can take 4-6 weeks or more.
William H Theodore MD, NINDS NIH 10/7D43
The NIH shared in a webinar on 4/6/2020 a summary update regarding the: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
- There were no significant differences in the effects of placebo and SGS-742 on neuropsychological tests or Transcranial Magnetic Stimulation (TMS).
- There were no significant differences in the side effects.
- The study drugs were well tolerated at the doses used.
- The neuropsychological tests were hard for some participants to do.
- The TMS generally went well.
Dr. Theodore went on to say that:
The drug dose was chosen based on a prior adult study using SGS-742 and at a level that would be tolerated by children. We don’t know for sure, but we don’t think a higher dose would have made a difference.
In a condition like SSADH the treatment will be much more likely to work if the drug was started at a younger age.
Additionally, this is a complicated condition with a number of abnormalities that SGS-742 would not have any influence on.
The drug may have a better effect with a combination of drugs, but that would have to be worked out on an animal before more human drug testing would be done.
Dr. Theodore then agreed to answer any questions that the participants had.
When asked about the magnetic resonance spectroscopy (MEG) testing he said that they will review this, but there were only a small number of participants who were able to complete this test.
Asked if anything was done with the urine and blood, he said no there we no tests to show the SGS-742 impact and neither were saved.
He also said only a few participants were willing to have a spinal tap and that fluid was sent to Dr. Mike Gibson to review.
When asked if the neuropsychological testing was broken down by OCD, attention, behavior conditional, etc, he said no the only test that they were able to gather any statistical data on was the Adaptive Behavior Assessment System (ABAS) tests.
He said he will check with the IRB to see if he is able to share with the families when their child was on the placebo and when they were on the SGS-742.
When questioned on specific test results that display on the NIH results page for an EEG test from baseline, Dr. Theodore commented that the TMS results were similar and consistent to prior SSADH studies at the NIH but didn’t show a significant improvement or a trend while they were on SGS-742.
When asked, how SGS-742 could have produced such good results in the mice and not the humans, Dr. Theodore said this often happens.
Dr. Pearl said that they are continuing to learn more from the current Natural History Study that is currently going on at Boston Children’s Hospital and he regrets having to have postponed the scheduled July SSADH conference. Perhaps they will be able to do a mini webinar to update the SSADH families on other ongoing research
This is the link to the results that were posted on the NIH web site regarding the SGS-742 trial.
Dr. Theodore and Dr. Schreiber will be publishing the results of the trail in a currently undetermined publication at a future date.
Unfortunately through the entire webinar Dr. Gibson was unable to comment as he was connected to the webinar as a participant and not a presenter.
Our next steps are:
Get access to the webinar for all SSADH families.
Get access to individual medical records for each participant in the SGS-742 Trial.
Get access to the raw data from the Technology Transfer Department at NINDS.
Natural History Study of Patients With Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
The Succinic Semialdehyde Dehydrogenase Deficiency (SSADH) Natural History Study Group of Drs. Gibson, Pearl, DiBacco, Krischer, Roullet, Opladen and Jeltsch, are officially opening their National Institutes of Health (NIH) - funded clinical study of patients with SSADH for enrollment.
The goal of the research team is to pioneer the first-ever description of the natural course of the disorder, find blood markers that will help in predicting disorder progression, monitoring treatment, and develop a newborn screening test to help end the challenging process for SSADH being diagnosed. Importantly, this study will help pave the way for FDA (Food and Drug Administration) approval of future medications to treat SSADH. Participation is limited but being offered at multiple sites, including Boston Children's Hospital in the United States as well as many other locations around the world. Participation is open to any patient with a confirmed diagnosis of SSADH, regardless of age and gender.
All are strongly encouraged to participate in the study. Simply email Dr. DiBacco or Jeltsch, their contact information is provided below, to get more information or to enroll. Your primary care doctor may also be able to help put you in contact with the research team.
The SSADH Association is fully supporting this study. We believe this study is a unique opportunity to learn more about SSADH, raise awareness about SSADH among doctors and other health care professionals, and provide a solid foundation for future clinical trials.
Additionally, this study will give you the chance to interact with the most experienced and knowledgeable SSADH medical professionals in the world. You will get a better understanding of SSADH and how SSADH is affecting your child. Please consider participation in this important study.
For more information or to enroll in the study please email:
Study Coordinator: Dr. Melissa DiBacco by email at: Melissa.Dibacco@childrens.harvard.edu
Study Coordinator: Dr. Kathrin Jeltsch by email at: Kathrin.Jeltsch@med.uni-heidelberg.de
Feel free to email me with any additional questions that you might have at: firstname.lastname@example.org
Natural History Study of Patients With Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
The study will be conducted by 4 academic institutions: Washington State University (WSU), Boston Children's Hospital (BCH), University of South Florida (USF), and University Children's Hospital Heidelberg (iNTD). The design of the study is mixed, with longitudinal and cross-sectional assessments over a period of 5 years.
Patients will be separated into three cohorts. The Boston Children's cohort will be a total of 20 patients in the United States. These patients will be followed for five years, and attend a visit to the hospital in years 1,3 and 5 where assessments including history/physical, neuropsychological testing, EEG, TMS, and bio-specimen collection will be completed. Each patient will have an MRI of the brain done with special GABA sequencing one time over the five years. Each visit will take place over the course of two days. At BCH, the goal will be to schedule visits every other year with questionnaires and surveys sent out up to every 6 months, and bio-specimen collection every year. The BCH team will also ask for two follow up phone calls occurring 12 months after each onsite visit. Visits will consist of clinical assessments (demographics, medical history, physical examination, neurological exam, medication history, neuropsychological assessments, and clinical severity score), neurophysiological assessments (Brain MRI/MRS/DTI, Electroencephalogram, and Transcranial magnetic stimulation), and yearly bio-specimen collection (blood, urine, saliva, hair, stool, and skin biopsy). Bio-specimens will be sent to Washington State University for testing and addition to a biorepository.
The iNTD (international NeuroTransmitters Disorders) cohort will be comprised of 15 patients who are seen at European sites who will have approval through their ethics committee to share de-identified information. Bio-specimens will be attempted to be collected at each visit from patients and sent to Washington State University. At the iNTD sites and for patients followed outside of iNTD, visits and bio-specimen collections will depend on the patients' follow-up schedules with electronic, web-based survey sent on a regular schedule (every 6 months).
The standard of care cohort will be comprised of 10 patients throughout the world who provide consent to their primary care physician to share de-identified information to the database.
The data will be stored in a database on the University of South Florida server. The server is password protected, and each member of the study personal will have a unique log in to have access to the site. Subjects will also be given specialized access to complete follow up electronic web based surveys twice a year over the course of 5 years. The team at USF will assist with data analysis.
This study will begin recruiting patients in early 2019, pending final IRB approval.
$1.58 Million grant awarded to Mike Gibson, PhD. from the NIH National Eye Institute
One drug known as Vigabatrin or Sabril (brand name) has been used in some cases of SSADH to help control seizures. However, Vigabatrin also has a severe side-effect known as night blindness which could potentially cause patients to permanently lose some degree of their peripheral vision if they take the drug long term.
The goal of this four year grant awarded to Dr. Gibson and a group of his colleagues, is to find a way to counteract that visual side effect of Vigabatrin.
2015 - 2018
Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
The primary outcome measures for drug efficacy will be performance on neuropsychological testing and responses to parent questionnaire. The secondary outcome measure will be TMS parameters of cortical excitation and inhibition. The outcome measures for safety will include clinical examination and neuropsychological tests.
2012 - 2014
Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA
The objective of this open-label taurine study was primarily to assess the effect of taurine on adaptive behavior and secondarily to collect safety and tolerability data in patients with succinic semialdehyde dehydrogenase deficiency.
A single case of taurine therapy for 12 months in a 2-year-old boy with SSADH deficiency showed improved socialization, behavior, coordination, and activity. This trial was an open-label trial with collection of baseline and follow-up data, preparatory to a randomized controlled trial utilizing biomarkers. The aim of this study was to assess the effect of taurine on adaptive behavior in SSADH deficiency.
2005 - 2008
Brain Excitability in Patients With Succinic Semialdehyde Dehydrogenase Deficiency
This study used brain imaging to map brain cell receptors for a chemical called GABA, a chemical that inhibits the activities of nerve cells. The study included patients with succinic semialdehyde dehydrogenase deficiency, or SSADH, their parents, and healthy volunteers.
The participants under went: Transcranial Magnetic Simulation (TMS), Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), Sleep Study and Multiple Sleep Latency onset Testing (MSLT) and Nerve Conduction studies.
2005 - 2008
PET Imaging of GABA Receptors in Succinic Semialdehyde Dehydrogenase Deficiency
This study used brain imaging to map brain cell receptors for a chemical called GABA, a chemical that inhibits the activities of nerve cells. The study includes patients with succinic semialdehyde dehydrogenase deficiency, or SSADH, their parents, and healthy volunteers.
Participants under went magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning.