Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber’s disease

SMA-PME and Farber’s disease are ultra-rare lysosomal diseases linked to mutations in the ASAH1
gene coding for ceramidase, an enzyme involved in the metabolism of a specific class of
lipids,ceramides. In the absence of this functional enzyme, ceramides accumulate in tissues, causing
severe dysfunction in several organs. The life expectancy of SMA-PME patients does not exceed
adolescence. Farber’s disease has more varied spectrum, from rapidly progressive disease leading to
death in the early years of life, to rarer forms characterized by slowly progressive disease onset in
adulthood. There is no treatment for these diseases.

Patients with SMA-PME suffer from degeneration of motor neurons in the spinal cord, the neurons
that control muscle contraction. When these motor neurons no longer function, they in turn cause
paralysis and hypotrophy of the muscle fibers they innervate. This causes difficulty in walking, with
progression to more generalized damage and respiratory failure. These patients also have myoclonic
epileptic seizures, i.e. sudden and brief contractions of some or all muscles. These seizures generally
appear in childhood, and increase in frequency with age.

Patients with Farber’s disease suffer from neurological and visceral damage, associated with the
appearance of subcutaneous nodules, joint deformities and a hoarse voice.

SMA-PME : Genethon’s work

Since 2019, Ana Buj Bello’s “Neuromuscular diseases and gene therapy” team at Genethon has been
working on the development of a gene therapy for patients with SMA-PME or Farber’s disease, in
association with the ASAP for Children association.

This work has led to the development of a drug candidate. Administered to mice with ceramidase
deficiency, the product developed by Genethon significantly improves the lifespan of treated
animals, and bring an overall correction of symptoms.

Based on these results, Genethon’s teams carried out the regulatory studies required to prepare a
clinical trial. The drug candidate was produced under Good Manufacturing Practice (GMP) conditions
at Yposkesi.

SMA-PME, Farber’s disease: latest information

In 2023, at the request of the referring physician and the family of a patient suffering from SMA-PME
at a very advanced stage of the disease, the Agence Nationale de Sécurité du Médicament et des
Produits de Santé (ANSM, French Regulatory Agency) gave an authorization for compassionate
treatment with the gene therapy product developed by Genethon. In accordance with regulations,
this authorization was given on the basis of the available data and the particular situation of this
patient. In making their decision, the family and the patient were provided with in-depth information
on the product and its potential benefit-risk ratio.

Six days after treatment, the patient died. Investigations are ongoing into the precise causes of death
and the role played by the gene therapy treatment. Once the results of these investigations are established, they will be published and be made available to the scientific and medical community, as
well as to patients.