Potential drug target for SPG4 identified
New assays (tests) allowing rapid detection of 3 important HSP features (phenotypes) in neurons derived from stem cells have been developed.
A potential drug treatment, a liver X receptor (LXR) agonist that reversed the impairment in all three features has been identified.
Axonal degeneration is a key pathology of neurodegenerative diseases, including hereditary spastic paraplegia (HSP), a disorder characterized by spasticity in the lower limbs. Treatments for HSP and other neurodegenerative diseases are mainly symptomatic.
While iPSC-derived neurons are valuable for drug discovery and target identification, these applications require robust differentiation paradigms and rapid phenotypic read-outs ranging between hours and a few days. Using spastic paraplegia type 4 (SPG4, the most frequent HSP subtype) as an exemplar, we here present three rapid phenotypic assays for uncovering neuronal process pathologies in iPSC-derived glutamatergic cortical neurons.
Specifically, these assays detected a 51% reduction in neurite outgrowth and a 60% increase in growth cone area just 24 hours after plating; axonal swellings, a hallmark of HSP pathology, were discernible after only 5 days. Remarkably, the identified phenotypes were neuron subtype-specific and not detectable in SPG4-derived GABAergic forebrain neurons.
We transferred all three phenotypic assays to a 96-well setup, applied small molecules and found that a liver X receptor (LXR) agonist rescued all three phenotypes in HSP neurons, providing a potential drug target for HSP treatment.
We expect this multiparametric and rapid phenotyping approach to accelerate development of therapeutic compounds for HSP and other neurodegenerative diseases.
SOURCE: Sci Rep. 2019 Jul 3;9(1):9615. doi: 10.1038/s41598-019-45246-4. PMID: 31270336
Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons.
Rehbach K1,2,3, Kesavan J1, Hauser S4, Ritzenhofen S1, Jungverdorben J1,5,6, Schüle R4,7, Schöls L4,7, Peitz M1,5, Brüstle O8.
1 Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, 53127, Bonn, Germany.
2 LIFE & BRAIN GmbH, Cellomics Unit, 53127, Bonn, Germany.
3 Icahn School of Medicine, Mount Sinai, 10029, New York, United States.
4 German Centre for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany.
5 German Centre for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
6 Memorial Sloan Kettering Cancer Centre, 10065, New York, United States.
7 Department of Neurodegenerative Diseases, University of Tübingen, 72076, Tübingen, Germany.
8 Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, 53127, Bonn, Germany. [email protected].
I am very interested to know more. I have had happy for a very long time. I have been in a wheelchair since I was 16 I am now 37 years of age. Any new information is welcomed. I have been under Dr. John Fink in Michigan for many years.
Very encouraging news for our relatives and descendents.
Case studies needed? When will more information be available?
I have HSP. I am 45 years old and was diagnosed with having HSP at 31. I am struggling with this terrible disease. I am a spg4, will we be able to try these drugs soon? Please say yes!!!
With this finding will it be possible to study hsp spg 8. Hopefully it too can have positive outcomes.
What is the drug called and when do you think it will be available for us to try? I need some hope! I am SPG4!!!
What is the name of the drug
Can you please explain which is the drug and how it works.
Secondly I have tried noscapine it’s of no use I will be saying it does not do anything I have common type of hsp may be type 4 now I am trying riluzole.
Can riluzole restore axonal function in case of uncomplicated type of hsp.
I have researched a lot on riluzole for axonal defects it has articles of positive findings.
And from past 1 month I am taking riluzole to see whether it helps…I’ll be at least trying for 6 months to see the results.
I have HSP and I want to know what I can do to improve my condition? I’m a 43 year old male. This really has me depressed and sad all the time. I’m still walking but barley I use a walker or sometimes use have to get my my jazzy. Thank you
Editor’s Note: Researchers often refer only to a class of compound for a potential drug candidate. This is done because the drug is a long way from being available for trial in humans, let alone approval and availability on prescription or otherwise. They may also wish to protect intellectual property. The compound is often not approved for any medical application and may not have been tested in any human clinical trial.