Progranulin haploinsufficiency (PGRN) is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Haploinsufficiency means that the produced protein is in a form that is unable to fill its biological roles. We are discussing a new article on this subject because potentially this therapy could also be applied to ALS.
Several therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of therapeutic approaches aimed at alleviating pathologies associated with FTLD could be their ineffective diffusion across the blood-brain barrier.
A fairly common strategy is to develop an adeno-associated virus (AAV) targeting the liver to achieve sustained peripheral expression capable of entering the brain. This was experimented in two mouse models of FTLD-GRN, namely Grn knockout and GrnxTmem106b double knockout mice.
This is what a drug (DNL593) from the company Denali Therapeutics does. It is administered intravenously, the viruses attach to the liver, the cells of which they exploit to generate the PGRN protein fused to a segment of antibodies that binds to the transferrin receptor, thereby facilitating transcytosis of transfer across the BBB.
Potential issues include short half-life, potential association with autoimmunity], risk of PGRN overexpression in the periphery and potential off-target effects, BBB permeability, and the possibility that the fusion protein may affect PGRN processing in the lysosome.
This therapeutic strategy, however, avoids the potential safety and biodistribution issues of AAV administered directly into the CNS while maintaining a level of PGRN in the brain after a single dose.
PGRN treatment reduced several pathologies commonly associated with FTLD-GRN in mice models of frontotemporal lobar degeneration, including severe deficits in motor function, aberrant TDP43 protein solubility and phosphorylation, and dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain.
Although AAV-type gene treatments are often associated with disastrous side effects such as hepatotoxicity, here a priori the mice did not suffer from side effects detectable by scientists.
The translatability of these results was confirmed in human induced pluripotent stem cells (hiPSCs). As was the case in mice, aberrant TDP43 levels, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with an exogenous TfR-binding protein transport vehicle fused to PGRN (necessarily different from the therapy administered to mice).
These studies suggest that peripherally administered brain-penetrating PGRN replacement strategies can ameliorate relevant FTD GRN phenotypes (there are other FTDs phenotypes that it can't ameliorate), including TDP-43 pathology, neurodegeneration, and behavioral deficits.
It should be noted that most of the authors are employees of the Denali company, so this fact must be taken into account when assessing the results. Another aspect is that several clinical trials are launched for the use of progranulin during FTD, we could perhaps see progress within a few years.