Research
The Carter Foundation’s mission is to enable the development of therapies and treatments for children with Hereditary Spastic Paraplegia (HSP). It is currently focused on the two most common forms of HSP, SPG3A and SPG4, with emphasis on those mutations with early age of onset and often de novo conditions.
The Foundation’s effort is to close the gap between the basic cellular and genetics understanding of those conditions and the development of therapies. This is called Translational Medicine. This means taking the current basic science understanding of these conditions and proving out therapeutic hypotheses in living animal models. With a reproducible animal model(s), formal therapeutic development and clinical trials may be undertaken by biopharma companies and institutes.
In this video, Drs. Blackstone and Avellone discuss the the latest developments from the Carter Foundation Research Program which is studying the following four therapeutic hypotheses in the SPG3A mouse model developed at Jackson Laboratories:
– Lipid modulation agents
– Bone Morphogenic Protein (BMP) signaling pathway inhibition
– Antisense Oligonucleotide (ASO) therapies
– Advanced gene editing (base editing)
Expected timeframe: 1-2 years. However, as any promising early results are noted, the plan will be to start discussions with relevant biopharmaceutical firms and institutes in parallel.
Dr. Craig Blackstone is the Chief of the Movement Disorders Division at the Massachusetts General Hospital (MGH) and a Professor of Neurology at Harvard Medical School. Prior to coming to MGH in 2020, Dr. Blackstone spent 20 years at the National Institutes of Health, ultimately as Senior Investigator and Cell Biology Section Chief within the Neurogenetics Branch. Under his leadership, his group investigated the cellular and molecular mechanisms underlying inherited movement disorders. He is one of the world’s leading investigators in this field.
Dr. Joseph Avellone a retired surgeon and healthcare executive, has a grandson, Carter, who has de novo complex SPG3A. He, along with other family members, founded the Carter Foundation for Neurologic Research.
Dr Darius Ebrahimi-Fakhari from Boston Children’s Hospital is building a registry of all childhood onset Hereditary Spastic Paraplegias (Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia).
Natural history studies are critical for rare diseases. Without them, treatment options will not be available. Future clinical trials related to cures for childhood HSP, including those that might arise from the research program of the Carter Foundation for Neurologic Research, will likely rely on this registry.
The study is still seeking participants globally. As of August 2022, the registry had only 11 SPG3A cases.
If you have SPG3A and haven’t yet registered, we highly recommend you reach out to
Amy Tam, the Study Coordinator, on her email:
amy.tam@childrens.harvard.edu
Participation is FREE and involves a 1 hour Zoom consultation with Dr Darius.
Inclusion criteria:
- Onset of hereditary spastic paraplegia symptoms before the age of 18 years
- Current age under 30
- Having variants in HSP related genes and/or a relative with such a diagnosis
Dr Craig Blackstone from Massachusetts General Hospital in Boston is one of the leading researchers in HSP, specifically SPG3A.
In collaboration with the Carter Foundation for Neurologic Disease Research, he is testing, both on in vitro and in vivo models, various drug compounds and gene therapy methods with a view to designing clinical trials in children with de novo SPG3A in the near future.
You can watch the presentation of Dr Blackstone research here, starting on minute 24:32 : https://videocast.nih.gov/watch=44694
Here is a snapshot from his presentation:
Dr Blackstone and the Carter Foundation will rely on the Boston Children’s HSP Natural History Study (described above) to design any future clinical trials.
Researchers Julian E Alecu, Afshin Saffari, Catherine Jordan, Siddharth Srivastava, Craig Blackstone, Darius Ebrahimi-Fakhari performed a cross-sectional analysis of 537 SPG3A patients, including 31 with de novo ATL1 variants.
They identified that certain variants, located within a three dimensional mutational cluster, cause more severe symptoms that go beyond pure HSP affecting only lower limbs. The more complex symptoms include neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms (dysarthria, dysphagia, etc.) , peripheral neuropathy and brain imaging abnormalities.
The variants they identified in this cluster are Ala350, Arg403, Arg415, Arg416, Asn355, Gly409, Gly410, Leu401, Lys407, Met347, Met408, Phe413, Pro344, Ser346, Ser398, Ser414, Tyr417, Val405.
Their findings establish a genotype-phenotype relationship for ATL1 mutations. This mutational cluster will inform future treatment options.
You can read the abstract here.
