CONICET-UBA: Achievement on key progress against a serious genetic disease

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Specialists from CONICET and UBA managed, in vitro studies, to stabilize defective proteins associated with Friedreich’s ataxia, a degenerative disorder that still has no cure. The work, which is part of a line of research that has an international grant, opens up new therapeutic possibilities.

Interaction between frataxin (key protein in Friedreich’s ataxia) and a nanoantibody (in red and blue) Image credit: María Florencia Pignataro, Juan A. Hermoso, Lorena Itatí Ibáñez, Javier Santos et al..

There are treatments that reduce its progression, but for now there is no cure for Friedreich’s ataxia (FA), a genetic disease that affects approximately one in every 50,000 people and is characterized by progressive damage to the nervous system and cardiological complications.

Scientists from CONICET and UBA managed to develop for the first time specific nanoantibodies that, inside cells, were capable of binding to the target protein whose deficiency generates this degenerative disorder. The advance, described in the journal Communications Biology, lays the foundation to explore the development of an innovative therapeutic strategy for this pathology.

Likewise, the laboratory of CONICET researcher Javier Santos, one of the leaders of the advance, received an international subsidy from the Friedreich’s Ataxia Research Alliance (FARA) to continue advancing this line of work.

“The molecular cause of Friedreich’s ataxia (FA) is the decrease in the expression (production) of the frataxin protein or the expression of variants with altered function or stability. In this new work we managed to stabilize these pathological proteins in in vitro studies (in isolation) and inside human cells. Currently, “We are working with cells donated by patients through hospital biobanks,” says Santos, co-leader of the advance and researcher at the Institute of Biosciences, Biotechnology and Translational Biology (iB3-FBMC), which depends on the Faculty of Exact and Natural Sciences of the UBA. “The progress encourages us to deepen this line of research with the hope of contributing to the development of therapeutic strategies that are superior, effective, and accessible to people.” he adds.

Javier Santos, one of the leaders of the advance, and María Florencia Pignataro, first author of the work, are researchers from CONICET and the UBA. Image credit: The Researchers

Nanoantibodies generated in camelids
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The main characteristic of Friedreich’s ataxia is an alteration in the genes that limits the manufacture or results in the production of functionally defective forms of frataxin that is in the mitochondria (metabolite and cofactor factories and energy plants of the cells).

The first step in this work was to immunize a llama. The animal was injected with the wild variant of frataxin of human origin so that his immune system generated heavy chain antibodies (VHH domains) with the capacity to bind specifically to correctly folded conformations. The immunization was carried out at INTA Castelar with the collaboration of CONICET scientists Viviana Parreño and Marina Bok.

In addition, the research group is developing very special variants of these nanoantibodies with international support.

“The nanoantibodies that we will use in the continuation of this work are small molecules derived from antibodies manufactured by the immune system of camelids. They have the ability to penetrate cell membranes, locate in mitochondria and stabilize defective frataxin proteins,” explains María Florencia Pignataro, first author of the work and CONICET researcher at iB3. “Nanoantibodies constitute a useful and versatile tool to interact with proteins within the cell due to their small size and high affinity.” she adds.

Along these lines, Santos states that “another interesting aspect of our research is that we observed that the expression of nanoantibodies and their mitochondrial localization does not affect certain cellular variables such as viability, cellular respiration and other functions. This information is encouraging if we think about possible therapies based on nanoantibodies.”

For Itatí Ibáñez, co-leader of the work and CONICET researcher at the Institute of Physical Chemistry of Materials, Environment and Energy (INQUIMAE, CONICET-UBA), “the small size of the nanoantibodies allows a single gene therapy vector to carry several of them or incorporate multivalent formats, which represents a significant advantage over other therapeutic molecules.”

Itatí Ibañez, also leader of the work and researcher at CONICET and the UBA. Image credit: The Researchers

Furthermore, states the researcher, “nanoantibodies can be modified very easily to favor their penetration into tissues and cells, thus expanding their potential and facilitating their application as therapeutic agents. It is a highly versatile tool, with a growing interest in both biotechnology and clinical applications and with a lot of potential to be developed as medicinal specialties for Friedreich’s ataxia.”

The knowledge obtained in this work “could help identify new therapeutic strategies to restore mitochondrial function in tissues affected by Friedreich’s ataxia,” highlights Santos. And concludes that “we will continue with more research with the aim of testing this strategy in preclinical models, a prior and crucial step to evaluate its safety and efficacy in clinical trials.”

To obtain cells from patients, the research team maintains a collaboration with the Italian Hospital of Buenos Aires, with doctors Diego Santoro, Marcelo Ielpi and Leandro D. Burgos Pratx, coordinators of the Biobank. Likewise, they worked in cooperation with the laboratory of Juan Antonio Hermoso at the Institute of Chemistry-Physics “Blas Cabrera”, in *Madrid, Spain.

Also participating in the work were: Antonella Vila, Hernán G. Gentili, Natalia Brenda Fernández, Alba Garay-Álvarez, Naira Antonia Rodríguez, Augusto E. García y Julián Grossi, from iB3 and the Department of Physiology, Molecular and Cell Biology (DFBMC, FCEN-UBA); María Florencia Pavan, from INQUIMAE; Martín Noguera, from “Prof. Alejandro C. Paladini” Institute of Biological Chemistry and Physicochemistry (IQUIFIB, CONICET-UBA); Martín Aran, from CONICET and the Leloir Institute Foundation (FIL); Rafael Molina, from “Blas Cabrera” Institute of Physical Chemistry; and Inés G. Muñoz, National Cancer Research Center (CNIO), in Madrid, Spain.

Also participating in the work were Antonella Vila, Hernán G. Gentili, Natalia Brenda Fernández, Alba Garay-Álvarez, Naira Antonia Rodríguez, Augusto E. García and Julián Grossi, from iB3 and the Department of Physiology, Molecular and Cellular Biology (DFBMC, FCEN-UBA); María Florencia Pavan, from INQUIMAE; Martín Noguera, from the “Prof. Alejandro C. Paladini” Institute of Biological Chemistry and Physicochemistry (IQUIFIB, CONICET-UBA); Martín Aran, from CONICET and the Leloir Institute Foundation (FIL); Rafael Molina, from the “Blas Cabrera” Institute of Physical Chemistry; and Inés G. Muñoz, from the National Cancer Research Center (CNIO), in Madrid, Spain.

Citation
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The paper Nanobodies as tools for studying human frataxin biology was published in Communications Biology Authors: María Florencia Pignataro, Natalia Brenda Fernández, Alba Garay-Alvarez, María Florencia Pavan, Rafael Molina, Inés G. Muñoz, Julián Grossi, Martín Noguera, Antonella Vila, Augusto E. García, Hernán G. Gentili, Naira Antonia Rodríguez, Martín Aran, Viviana Parreño, Marina Bok, Juan A. Hermoso, Lorena Itatí Ibañez & Javier Santos
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