Cure AP-4: For a future as bright as their smiles

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: NCT04712812

A 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 is pursuing a drug screening experiment on fibroblasts derived from AP-4 related HSP patients. The process begins with obtaining skin cells from the patient and the same gender parent. IPSC stem cells are developed from the tissue, and then differentiated into central motor neuron cells which can be maintained and studied in a lab. The goal of the project is to test whether various compounds which are FDA-approved for other disorders might offer some benefit to the cells affected by AP-4 related HSPs. Potentially, the drug screening research may help identify a treatment which benefits all of four of these diseases. 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 has engaged Dr. Mimoun Azzouz of the University of Sheffield to develop a gene therapy proof-of-concept for SPG47. His team has developed an AAV9 viral vector capable of delivering a good, working copy of the AP4B1 gene to the central motor neurons of a knockout mouse as well as fibroblasts derived from SPG47 patients. If successful, this research will provide the basis for pursuing human clinical trials in the coming years. Early proof-of-concept research looks promising thus far.

Cure AP-4 has partnered with Unravel BioSciences, Inc. ("Unravel") to identify potential therapeutics for AP-4 hereditary spastic paraplegia.

Unravel, a pioneering therapeutics company leveraging a machine-learning network model of whole body human health to accelerate the development of drugs for complex diseases, will utilize its in silico predictive drug discovery platform called BioNAV™ to accelerate drug discovery for AP-4 by collecting RNA data from families and patients around the world to identify potential treatments specific to patient subgroups.

The funding will support Unravel to generate RNAseq data from diverse AP-4-HSP patients across the globe to stratify patients by therapeutic response and deploy its BioNAV™ computational platform for in-depth in silico compound screening and target discovery. Additionally, RNAseq data from mouse models will be used to plan preclinical studies for each patient subgroup. This initiative aims to uncover and forecast effective treatments that would benefit patients through rapid repurposing of existing drugs, while strategically enabling Unravel to uncover new targets and develop novel therapeutic molecules for AP-4-HSP.

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

Our goal is to make the process as easy as possible for you. By clicking on the link below, you can learn more about this one-of-a-kind Data Collection Program and begin the first step in making your child's patient information available to researchers.

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?

Their aim is to empower advocates to take insights to patient advocacy organizations, pharmaceutical companies, and regulatory agencies to drive change for patient communites.

Additional AP-4 HSP Research Publications:

Research

Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP)

Participant enrollment entails:

For Medical Professionals:

Current AP-4 HSP Research Projects:

Additional AP-4 HSP Research Publications:

Nature Communications

Neurology

Brain Communications

BioRxiv

Protein Science

Clinicaltrials.gov

GeneReviews®

Human Molecular Genetics

Annals of Clinical and Translational Neurology

Brain

Neurology Genetics

Brain

Stem Cell Research

Nature