Cell mechanism behind SPG7 discovered

Drug treatment to correct impairment identified

The nature of the disease-causing process involving the mitochondrial network in SPG7 has been discovered using both cells from people with SPG7 and mice with SPG7 in experiments.

Drug treatment with the benzodiazepine Bz-423 normalises nerve impulses and restores mobility in the SPG7 mice, so establishing the potential for a therapy for SPG7.

Prof Casari

Background: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motor neuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca2+ and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function.

Methods: We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423.

Findings: We demonstrate that paraplegin is required for efficient transient opening of the mPTP that is impaired in both SPG7 patient-derived fibroblasts and primary neurons from Spg7-/- mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model.

Interpretation: mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia.

Funding: Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18-1-0001.

SOURCE: EBioMedicine. 2020 Oct 9;61:103050. doi: 10.1016/j.ebiom.2020.103050. Online ahead of print. PMID: 33045469 Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia

Irene Sambri  1 Filomena Massa  1 Francesca Gullo  2 Simone Meneghini  2 Laura Cassina  3 Michela Carraro  4 Giorgia Dina  3 Angelo Quattrini  3 Lorenzo Patanella  1 Annamaria Carissimo  5 Antonella Iuliano  1 Filippo Santorelli  6 Franca Codazzi  7 Fabio Grohovaz  7 Paolo Bernardi  4 Andrea Becchetti  2 Giorgio Casari  8

  1. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy.
  2. University of Milano-Bicocca, Milan, Italy.
  3. San Raffaele Scientific Institute, Milan, Italy.
  4. University of Padua, Padua, Italy.
  5. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy; Institute for Applied Mathematics ‘Mauro Picone’, National Research Council, Naples, Italy.
  6. RCCS Fondazione Stella Maris, Pisa, Italy.
  7. Vita-Salute San Raffaele University, Milan, Italy.
  8. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli-Naples, Italy; Vita-Salute San Raffaele University, Milan, Italy


    1. Editor’s Note: The research reported is just the start of the process of trying to translate this important finding into a successful treatment. More studies on the mechanism will be carried out. More studies on the effect of the candidate drug on experimental animals with SPG7 will take place. There may be human stem cell studies in SPG7 to help assess the potential for the drug therapy.
      Only if and when the results of all that research is positive, could clinical trials be undertaken to determine the safety and effectiveness of the drug treatment in people with SPG7.
      So it is likely that this treatment, if proven successful, would not be available for at least a few years yet. Research developments will be reported on in the quarterly website updates as they are published.

    1. Editor’s Note: Given that SPGs 4 and 7 have a significantly different disease-causing mechanism, then, on the face of it, possibly not. However, the demarcation lines between different HSPs and different mechanisms is blurred rather than clear-cut, for example, mitochondrial impairment may be a factor in SPG4 based on some more recent research, where previously it was thought not to be. Also, there is massive disruption in gene expression associated with both SPGs 4 and 7, and it may well prove in time that a critical element in causing disease is shared between the two. Whether or not this candidate drug is the remedy though, only time, money and research studies will tell.

    1. Editor’s Note: The candidate drug identified for SPG4 in this Foundation’s research program is waiting to be tested in a clinical trial. Grant funding applications have thus far been unsuccessful – and such money would be needed as the cost of clinical trials has increased a lot since the COVID pandemic. There are also technical challenges – it would be great if there was a definitive marker and measure of disease status suitable for use in a clinical trial, and pre-clinical investigations are advancing on this, but again, more funding would greatly help accelerate this as well. Short of receiving some unexpected windfall, we do what we can to attract attention, raise awareness, apply for grant funding – and patiently wait in line with the other 7,000 rare diseases for our turn.

      There are very active research programs aiming to develop drug and gene therapies for SPG4 that are being watched closely. A gene therapy for SPG50 was administered to a child in North America last year with apparently good tolerance at last report, and again we are closely watching and hoping for positive outcomes there. Whilst it would be great if successful gene therapy for HSP could be developed, this can only be administered one person at a time and with a pricetag in the millions.

  1. I am 67 with SPG 7 (uncomplicated) and live in Canada.

    Hoping you are approaching clinical trials as I was was diagnosed in 2012 and continue to show increasing severity of symptoms. Walking with 2 sticks.

    1. Hi Mike,
      I have questions about SPG 7. My email is [not able to be shown]. It’ll be great to have a chat.

    1. Editor’s note: If you are referring to the SPG7 research, it is being conducted in Italy, so participants would be sourced locally if this leads to studies in people with SPG7. If your question is more general, join an HSP support group like this one in Australia or the SP Foundation in the US. Contributing funding support for HSP research is the primary way to help, to ensure research continuity and progress towards the development of cures.

    1. Editor’s note: The researchers are not naming the specific candidate drug compound, just saying that it is a type of benzodiazepine and giving it a codename Bz-423. A search of the literature has failed to produce any updates or further progress in research on this compound for SPG7, so it is a matter of waiting and watching. It would be expected to take several years at least before such a candidate drug would be available, if successful in further pre-clinical investigations and ultimately in clinical trials.

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