Biotherapy for familial amyloid polyneuropathies
le Kremlin Bicetre, France
49 slide(s) – 00:21:33 – English – 2011-09-11
- To know the principe of liver transplantation (LT) in familial amyloid polyneuropathy (FAP)
- To know the natural history of FAP : sensorymotor polyneuropathy, autonomic dysfunction and systemic manifestations including cardiac and ocular.
- To know of the effect of LT on survival, on the neuropathy, on the cardiopathy.
- To know the risks of LT in FAP.
Introduction: Familial amyloid polyneuropathies (FAP) are disabling progressive and life threatening disease with an autosomal transmission and are usually due to point mutation of Tranthyretin (TTR) gene. More than 40 TTR gene mutations have been identified. Liver is the main source of variant TTR which is amyloidogenic.
Objective: To focus on biotherapies which have been developed during last 20 years.
Results: Liver Transplantation (LT) has been first proposed in 1990 in Sweden to suppress main source of amyloid. More than 1550 FAP patients underwent LT, usually with a met30TTR variant. LT is able to reduce serum variant TTR level by 98 percent, the rate of myelinated axon loss in nerve biopsy specimens, to stop progression of met30TTR-FAP in 70 percent with a long follow-up and to double median survival : 21.6 y. vs 10.8. The results are less clear in nonmet30-TTR-FAP. Main morbidity includes infections. Contraindication for LT are low mBMI< 600, severe autonomic dysfunction or walking disability. Other biotherapies have been developed in transgenic mouse models for TTR-FAP including antisense oligonucleotides, lipid nanoparticles formulations of SiRNA to inhibit hepatic expression of TTR. SiRNA allow to reduce TTRmRNA in rodent, to suppress mutant protein level, and reduce mutant TTR in tissue. More recently Mab for human serum amyloid P (SAP) component assessed in murine AA amyloidosis removes massive visceral amyloid deposits.
Conclusions: Biotherapies are essential for treatment of FAP: LT is the treatment of choice for met30TTR FAP, other biotherapies show encouraging results. Phase I clinical trials are ongoing.