Research
Here is a map view depicting the location of patients enrolled in our research on Adapter-Protein 4 (AP-4)-related Hereditary Spastic Paraplegia at this time:Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP)
ClinicalTrials.gov Identifier: NCT04712812A team at Boston Children's Hospital, in partnership with Cure AP-4, has developed a translational research program for AP-4-associated hereditary spastic paraplegia (AP-4-HSP), a group of four ultra-rare genetic disorders:
| Gene | Hereditary Spastic Paraplegia |
| AP4B1 | SPG47 |
| AP4M1 | SPG50 |
| AP4E1 | SPG51 |
| AP4S1 | SPG52 |
This includes an international registry and a natural history study. The objectives of this research study are to (1) to systematically document the clinical presentation and natural history of AP-4-associated HSP and (2) to facilitate an early diagnosis, enable counseling and anticipatory guidance of affected families and help define clinically meaningful endpoints for future interventional traits.
Participant enrollment entails:
- Informed consent conversation via phone or Zoom
- Clinical history questionnaire
- Possible blood sample collection
There is no cost to participate and travel to Boston is not required. The enrollment can be completed remotely. The team works with interpreters for families who do not speak English. If you believe you or your child may be eligible for this study and you are interested in learning more, please contact:
Amy Tam
Research Coordinator
Translational Neuroscience Center | Boston Children's Hospital
Phone: 617-355-2698
E-mail: hsp.research@childrens.harvard.edu
Darius Ebrahimi-Fakhari, MD, PhD
Department of Neurology | Boston Children's Hospital
E-mail: darius.ebrahimi-fakhari@childrens.harvard.edu
More information about the Natural History Study can be found here:
https://clinicaltrials.gov/ct2/show/NCT04712812
More information about the AP-4-HSP program at Boston Children’s Hospital can be found here:
https://www.childrenshospital.org/conditions-and-treatments/conditions/a/ap-4-associated-hereditary-spastic-paraplegia
For Medical Professionals:
GeneReviews article on AP-4-associated hereditary spastic paraplegia:https://www.ncbi.nlm.nih.gov/books/NBK535153
Other resources:
https://pubmed.ncbi.nlm.nih.gov/32979048/
https://pubmed.ncbi.nlm.nih.gov/34544818/
https://pubmed.ncbi.nlm.nih.gov/29193663/
Current AP-4 HSP Research Projects:
The International Registry and Natural History Study for Adapter-Protein 4
(AP-4)-related Hereditary Spastic Paraplegia has shown that when any of the AP-4 subunit genes are
defective, the clinical phenotype is essentially the same. This connects a total of four SPGs: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) & SPG52 (AP4S1).
Dr. Darius Ebrahimi-Fakhari of Boston Children's Hospital oversaw the screening of over 30,000 FDA-approved drugs and experimental compounds for benefit in AP-4 HSP fibroblasts. The project yielded a handful of promising results, which are currently being pursued in a drug development program on AP-4 HSP knockout mice. The goal of this iterative process is to develop a compound that rescues ATG9A and DAGLB from the Trans-Golgi Network, which in theory, should restore downstream function including normal neuron growth. Potentially, the program may help identify a small molecule treatment which benefits patients of all four AP-4 HSP subtypes.
A detailed clinical characterization of SPG47 is available through the American Journal of Medical Genetics, and
an expanded clinical, molecular and imaging spectrum of AP-4 HSP is available through Brain - A Journal of Neurology.
Cure AP-4 engaged Dr. Mimoun Azzouz of the University of Sheffield to develop a gene replacement therapy proof-of-concept in 2017. His team successfully developed a viral vector capable of delivering a working copy of the AP4B1 gene to the central motor neurons of a knockout mouse. This program has been licensed by BlackfinBio, which is currently fundraising for human clinical trials.
In collaboration with Jack's Corner, Cure AP-4 engaged Unravel Biosciences for an AI-powered drug repurposing study based on disease pathways evident in RNA-seq data from AP-4 HSP patients and gender matched parents. The project has yielded a list of several FDA-approved drugs and nutraceuticals warranting further study. Currently, the high priority drugs are being trialed in AP-4 HSP tadpoles, with plans in the works for further testing in mice and humans.
The Cure AP-4 community is partnering with RARE-X [a 501(c)(3) nonprofit] to build a Data Collection Program for AP-4-HSP families/caregivers. When you participate in the AP-4-HSP Data Collection Program, you'll help accelerate research and the development of new drugs, devices, and other therapies.
The AP-4-HSP Community is building the AP-4-HSP Data Collection Program to...
- Inform researchers how AP-4-HSP changes over time
- Enable better data to use in clinical trials
- Give patients the opportunity to participate in clinical trials
- Reduce the time it takes to study new medicines
- Speed up the time to get treatments to patients
- Enable the use of data as a placebo (instead of actual patients) in a clinical trial
Link to AP-4-HSP Community Page
TREND Community is a digital health analytics company that partners with communities across rare, chronic, and emerging diseases to shine a light on the experiences of people living with these conditions.
TREND Community is partnering with Cure AP-4 via the family/caregiver group on Facebook.
They use natural language processing to analyze these conversations, which gives a broader and more authentic view of diseases and their management than we get from traditional research.
Via the TREND Share app on Facebook, they can provide data-driven answers to questions like:
- What symptoms are experienced?
- How are people managing their health conditions?
- What are the community's unmet needs?
Additional AP-4 HSP Research Publications:
Nature Communications
AP-4-mediated axonal transport controls endocannabinoid production in neuronsNeurology
Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4–Associated Hereditary Spastic ParaplegiaBrain Communications
High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegiaBioRxiv
AP-4 mediates vesicular transport of the 2-AG endocannabinoid producing enzyme DAGLBProtein Science
Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4Clinicaltrials.gov
Registry and Natural History Study for AP-4 Associated Hereditary Spastic Paraplegia (AP-4-HSP)GeneReviews®
GeneReviews®: AP-4-Associated Hereditary Spastic ParaplegiaHuman Molecular Genetics
Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein traffickingAnnals of Clinical and Translational Neurology
Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52: Loss of ap4s1 in Zebrafish Resembles SPG52Brain
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegiaNeurology Genetics
Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7Brain
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegiaStem Cell Research
Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47)Nature
AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A