Three Paths of Work, One Goal

What it is

A natural history study follows how a disease develops over time across many people — when symptoms start, how they change, and how quickly. No single clinic sees enough people with SPG76 to answer those questions.

Dr. Gan-Or's team has gathered the clinical details of published SPG76 cases from around the world into one dataset and, together with the SPG76 Research Foundation, is inviting the doctors who reported them — and others who follow people with SPG76 — to add follow-up information, such as the age when patients first needed a walking aid.

Who leads it

Dr. Ziv Gan-Or and his team at The Neuro (Montreal Neurological Institute-Hospital), McGill University.

Why it matters

You cannot tell whether a treatment slows or halts SPG76 without first knowing how it progresses without one. Describing how SPG76 progresses over time, and whether the specific CAPN1 change affects the course, is the baseline any future treatment study will need.

Where it stands

The published cases are gathered into one dataset, and the invitation to doctors has been prepared together. The invitations are sent by Dr. Gan-Or's team, and doctors share de-identified information directly with the research team. The foundation does not collect or hold any patient data.

About Dr. Gan-Or · How patients and doctors can take part

What it is

SPG76 is caused by changes in the CAPN1 gene, which means the body cannot make an enzyme called calpain-1. Without calpain-1, a related enzyme, calpain-2, is left unopposed, and this is thought to contribute to the damage to nerve cells. This path tests whether blocking calpain-2 with a selective inhibitor can protect the nervous system.

Who leads it

Dr. Michel Baudry, University Professor at Western University of Health Sciences in Pomona, California, who has studied calpains for more than 40 years.

Why it matters

It aims at what is thought to drive the damage in SPG76, not only at the symptoms. And a blood test of calpain-2 activity would let future studies see whether a treatment is reaching its target.

Where it stands

Preparing a study in mice that lack calpain-1 — the same change as in people with SPG76. A research funding application for this work is under review, and it is also part of the five-year Canadian program.

About Dr. Baudry

What it is

Because SPG76 is caused by the loss of a working gene, gene therapy aims to deliver a working copy of CAPN1 to nerve cells. No harmful protein needs to be silenced — only a missing one restored. The CAPN1 gene is small enough to fit within the delivery vehicles used for gene therapy, and people who carry one working copy are healthy, which suggests that even partial restoration could help.

Who leads it

A research network in Brazil is developing a gene-replacement approach for SPG76, working with patients' cells and the SPG76 mouse model. The same network runs a national study that follows people with hereditary spastic paraplegia over time, maps how the conditions progress, looks for markers in blood, imaging and digital measurements, tests the best ways to measure change, and builds the groundwork for future clinical trials.

The five-year Canadian program led by Dr. Gan-Or includes testing gene therapy in the SPG76 mouse model, with partner laboratories.

Why it matters

Gene therapy aims at the root cause. Gene therapy programs for other forms of hereditary spastic paraplegia have already worked through many of the same steps, so SPG76 can build on their experience rather than start from scratch.

Where it stands

Early laboratory research, in patients' cells and in mice.