Therapeutic Innovations

Our research unit develop therapies from preclinical research to clinical applications until the first sucessful therapy of life-threatening diseases.  The developped therapies concern mainly three main axes.

– Nanomedicine, based on the encapsulation of small interfering RNA (siRNA) to treat monogenic peripheral neuropathies and study the pathophysiological mechanisms involved in peripheral nervous system disorders (Leaders: Liliane MASSADE, David ADAMS).

– Novel therapies based on steroids (Leader: Michael SCHUMACHER)

– Genic therapy based on viral vectors to deliver genes treating various diseases (Leader: Catherine Le Stunff).

The clinical research relies teams of the Bicetre Hospital (close to Paris) for example on the clinical team of the Rare Diseases Reference Center (CRMR) of the CHU Bicêtre, APHP, is the only French reference center approved for rare neuropathies. As a result, patients with CMT, FAP, GBS and CIDP are referred from all over France to our CRMR for diagnosis and management expertise.

The preclinical research is part of the laboratories of excellence in nanosciences and nanotechnologies (LaBEX Nanosaclay, http://nanosaclay.fr).

Diagnosis and therapy of genetic and dysimmune peripheral neuropathies

PI: Andoni Echaniz-Laguna (Team 1/2)

Inherited neuropathies (NI) are the most common inherited neurological disorder, affecting at least 1 in 2,500 people. Although more common than amyotrophic lateral sclerosis, Parkinson’s disease and spinal muscular atrophy combined, NI is under-reported and largely under-recognized by the general public. Among IN, Charcot-Marie-Tooth disease (CMT) and familial amyloid polyneuropathy (FAP) are two major subgroups, representing 25,000 to 30,000 patients in France. Dysimmune neuropathies (DN) are rare conditions affecting the peripheral nerves and mainly include Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). The clinical team of the Rare Diseases Reference Center (CRMR) of the CHU Bicêtre, APHP, is the only French reference center approved for rare neuropathies. As a result, patients with CMT, FAP, GBS and CIDP are referred from all over France to our CRMR for diagnosis and management expertise. Our clinical team has conducted major works that have enabled breakthrough therapies for hereditary neuropathies.

Development of targeted therapies for monogenic neuropathies by siRNA therapeutics

Targeted therapies for peripheral neuropathies

PI : Liliane Massade (Dir. Team 2)

Our research is focused on the use of nanomedecine based on small interfering RNA (siRNA) nanoparticles for the treatment of monogenic peripheral neuropathies. The strength of our team relies on complementary expertises in: 1) siRNA design, their characterization and optimization; 2) nanotechnologies, with the development of nanoparticle carriers for the delivery of siRNA and neuroactive molecules.

Recently, we investigated the regulation of a gene playing a key role in inherited demyelinating peripheral neuropathy by siRNA-squalene nanoparticles. The effect of these nanoparticles were tested in a mouse model, characterized by muscle weakness and atrophy and by slow nerve conduction velocity (European patent filed in September 2018). Importantly, we showed a normalization of the disease gene expression in this mouse model in addition of the reversal of the disease process and symptoms.

The figure below represents our projects for the next years. They consist of optimization of the treatment by siRNA-squalene nanoparticules and studying the mechanisms underlying the restoration of motor activity in the model of inherited demyelinating neuropathy. Our final aim is to reach clinical phases that will be done in the National reference center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, headed by Pr. David ADAMS.

This work is supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d’Avenir” program (Labex NanoSaclay, reference: ANR-10-LABX-0035).

Therapy of  amyloid neuropathies

PI: Andoni Echaniz-Laguna (Team 1/2)

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis with polyneuropathy (also known as familial amyloid polyneuropathy) is a condition with adult onset caused by mutation of transthyretin (TTR) and characterized by extracellular deposition of amyloid and destruction of the somatic and autonomic peripheral nervous system, leading to loss of autonomy and death.  The pathophysiology of the neuropathy includes instability and proteolysis of mutant TTR leading to deposition of amyloid with variable lengths of fibrils, microangiopathy and involvement of Schwann cells. Wild- type TTR is amyloidogenic in older individuals. The main symptoms are neuropathic, but the disease is systemic leading to cardiac, eye and kidney pathology.

Until recently, disease modifying therapeutics that have been developed include liver transplantation and TTR stabilizers,
both of which can slow progression of the disease and increase survival in the early stages.

D. Adams (head of the Neurology Department of the Bicêtre Hospital and member of Team 2) has developped the first-ever siRNA therapeutic for the treatment ATTRv, in collaboration with Alnylam Pharmaceuticals (Adams et al., 2018). The siRNA product Patisiran (Onpattro) has been approved by American Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients after a successful Phase III trial.

Major problems faced by siRNA therapy are their rapid degradation and the difficulty to deliver the negatively charged nucleic acids to target cells. For Patisiran, the problems have been overcome by delivering the siRNA molecule in a lipid nanoparticle, able to cross the cell membranes. As transthyretin is mainly synthesized within the liver, where lipid nanoparticles naturally accumulate, the inhibition of transthyretin expression by siRNA has been successful. In a total of 148 Patisiran-treated patients compared to 77 placebo-treated patients, the almost 80% decrease in serum transthyretin levels significantly stabilized, and even improved neurological scores including gait over a 18 months period. Treatments were administered intravenously once every 3 weeks (Adams et al., 2018). Importantly, a longer-term safety and efficacy follow-up shows that patisiran maintains efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis (Adams et al., 2021).

Adams D et al. (2018) Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379:11-21 (https://doi.org/10.1056/NEJMoa1716153)

Adams D et al.  (2021) Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol 20:49-59  (https://doi.org/10.1016/s1474-4422(20)30368-9)

Mechanistic models of amyloid fibril formation and disease progression. a | Stability of transthyretin (TTR) homotetramers is reduced by TTR mutations, resulting in its dissociation into monomers and deposition in the extracellular spaces of systemic organs. The dissociation results in misfolding of TTR monomers and subsequent aggregation. These oligomers can be present before the completion of mature amyloid fibrils and can have toxic effects on neighbouring tissue. b | Disruption of the blood–nerve barrier (arrowhead; vessel lumen indicated by asterisk) can occur in the early phase of neuropathy , resulting in leakage of circulating TTR into the endoneurial space. Consequently, amorphous, electron- dense extracellular material that contains TTR monomers and oligomers becomes abundant in the extracellular spaces of the endoneurium. Aggregation of TTR is subsequently seen as dotty structures among amorphous materials. Finally , elongated fibrillar structures with a thickness similar to the diameter of the dotty structures are formed, leading to adjacent Schwann cell atrophy. (from Adams et al, Nat Rev Neurol, 2019)

Cerebroprotective effects of steroid hormons and of neurosteroids

PI : Michael Schumacher (Dir. Team 1)

Our teams share expertise in steroid neuroendocrinology and providing precise, sensitive and robust steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS). This expertise allow to use of steroids and other neuroactive signaling molecules to promote the regeneration of myelin. To improve the safety and efficacy of steroids for treating diseases and lesions of the nervous system, and for preferentially administering them to the brain and spinal cord, the intranasal delivery route is explored. The identication of the intracellular progesterone receptors as major players in actions of progesterone in neural cells has important therapeutic implications, opening the way for the use in neuroprotective and myelin repair strategies of synthetic progestins, developed for hormonal contraception and the treatment of endocrine disorders.