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Current Research: Projects That Spark Hope

Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disorder characterized by the conversion of the cellular prion protein PrP^C into its pathological form PrP^Sc, which aggregates, self-propagates and accumulates in the brain, triggering an irreversible neurodegenerative cascade and making the development of effective therapies difficult.

Although there is no curative therapy available to date, the scientific community is promoting multiple studies aimed at slowing the progression of the disease and improving the quality of life of patients. Below are summarized some of the main lines of research, with an indication of ongoing projects and experiments.

Drugs used so far: successes and failures

Over the years, anti-inflammatory drugs, antivirals, and therapies aimed at reducing prion production have been tested. Unfortunately, the results have not been enough to stop the disease. However, each failed trial has added a piece of knowledge, directing researchers towards new avenues of research.​​

A Glimmer of Hope: The Prion Alliance

The Prion Alliance is a nonprofit organization dedicated to funding and advancing scientific research aimed at finding a cure or effective therapy for prion diseases, particularly the genetic (inherited) forms of these diseases. Founded by Sonia Vallabh and Eric Minikel, the Prion Alliance was born out of a personal story: after Sonia's mother passed away due to an inherited prion disease, the couple decided to leave their previous career paths to dedicate themselves to prion research, studying at the Broad Institute and Massachusetts General Hospital (MGH) in Boston.

The main goal of the Prion Alliance

  1. Therapeutic Development: Funding and support for innovative research for rapid therapies, with a focus on prevention in carriers of genetic mutations.

  2. Prion biology: studies on the mechanisms of conversion of PrP^C to PrP^Sc to identify drug targets.

  3. Scientific Collaborations: International research network to accelerate progress through sharing data and expertise.

  4. Awareness and training: dissemination, early diagnosis, genetic counseling and promotion of scientific dialogue on prion diseases.

The CHARM project: focus and details

Sotto l’ombrello della Prion Alliance (e in sinergia con istituzioni di ricerca di alto livello), è stato lanciato il progetto CHARM, un’iniziativa che si concentra in particolare su strategie terapeutiche volte a “silenziare” o ridurre l’espressione del gene PRNP, che codifica la proteina prionica (PrP). Di seguito alcuni punti chiave:

  1. Approccio “gene silencing”

    • Il progetto fa ampio uso di tecnologie come gli antisenso oligonucleotidi (ASO) o potenzialmente l’RNA interference (RNAi), allo scopo di abbassare i livelli di PrP nelle cellule cerebrali.

    • L’idea di base è che, riducendo la quantità di proteina prionica normale (PrP^C), si limiti drasticamente la possibilità che questa si converta nella forma patologica (PrP^Sc).

  2. Focus su individui portatori di mutazioni

    • Particolarmente cruciale è il lavoro sui soggetti che hanno una mutazione genetica ereditaria nota per causare la malattia. Poiché molte forme di malattie prioniche si manifestano improvvisamente e progrediscono rapidamente, l’intervento prima dell’insorgenza dei sintomi è una delle strategie più promettenti.

    • CHARM mira a sviluppare terapie preventive che possano essere somministrate prima che la malattia si manifesti clinicamente, con l’idea di impedire la conversione patologica e, in prospettiva, salvare la vita delle persone a rischio.

  3. Sperimentazioni precliniche e collaborazione con aziende biotech

    • Il progetto è svolto in collaborazione con aziende farmaceutiche e biotech specializzate nello sviluppo di antisenso oligonucleotidi. Un esempio è la partnership con Ionis Pharmaceuticals (nota per il lavoro su terapie ASO in varie patologie neurodegenerative).

    • Vengono condotti test su modelli murini e su altre piattaforme sperimentali, in modo da valutare sia l’efficacia (riduzione stabile di PrP e prevenzione dei sintomi) sia la sicurezza (assenza di effetti tossici o impatto negativo su funzioni cerebrali).

  4. Validazione clinica futura

    • Una volta verificate la sicurezza e l’efficacia in modelli preclinici, l’obiettivo è avviare trial clinici su volontari ad alto rischio o in fase iniziale di malattia.

    • Il fine ultimo è dimostrare che, riducendo in modo controllato l’espressione della proteina prionica, si riesca a rallentare o bloccare la progressione della malattia prionica ereditaria (e potenzialmente di altre varianti sporadiche o acquisite).

  5. Innovazione e multidisciplinarietà

    • CHARM riunisce biologi molecolari, genetisti, neurologi, esperti di bioinformatica e clinici per affrontare le sfide di ricerca.

    • Attraverso lo studio dei meccanismi biologici e genetici delle malattie prioniche, il progetto punta non solo a sviluppare terapie, ma anche a identificare biomarcatori (indicatori misurabili di progressione o risposta al trattamento) e test diagnostici più precoci e affidabili.

This type of research has revolutionary potential: if successful, it could not only change the fate of those suffering from CJD, but provide new weapons against other neurodegenerative diseases, such as ALS, Alzheimer's and Parkinson's disease.

Ionis Pharmaceuticals' Experimental Drug ION717

An innovative therapeutic approach is based on the use of antisense oligodeoxyribonucleotides (ASOs) aimed at reducing the expression of the prion protein. In this context, Ionis Pharmaceuticals is developing the compound ION717, with the aim of selectively silencing the PRNP gene, responsible for the synthesis of PrP^C, thus preventing the conversion to PrP^Sc.

  • Working principle:
    ASOs bind to the messenger RNA of the PRNP gene, hindering its translation and decreasing the production of the native prion protein which, if altered, causes the pathology.

  • Trial and collaboration with the IRCCS Carlo Besta of Milan:
    The clinical trial is starting at the Fondazione IRCCS Istituto Neurologico "Carlo Besta" in Milan, a national reference center for rare neurodegenerative diseases, aimed at evaluating the safety, tolerability and possible efficacy of ION717 in patients with CJD. Currently, it is not possible to apply for "compassionate use" of the drug, as in the current phase of the trial (PHASE 2) the tolerability and not the efficacy of the drug is being evaluated.

The Use of Porphyrins: Evidence from the Mario Negri Institute

Compounds with potential anti-prion action include porphyrins, organic molecules implicated in numerous biochemical processes, including the synthesis of heme. According to a study conducted at the Mario Negri Institute for Pharmacological Research, some porphyrins have the ability to bind to PrP^Sc, hindering its propagation.​​

The aim of the study

Researchers have identified a tetracationic porphyrin, Zn(II)-BnPyP, which binds to two distinct domains of the prion protein PrP^C, inducing a dual anti-prion action:

  1. Inhibition of the conversion of PrP^C to PrP^Sc, destabilizing the native conformation of the prion protein.

  2. Induction of endocytosis and lysosomal degradation of PrP^C, reducing the substrate available for prion propagation.

Conclusions, perspectives and limitations

Lo Zn(II)-BnPyP è il primo composto noto ad agire contemporaneamente su due regioni distinte di PrP^C, inibendo la conversione a PrP^Sc e promuovendo la degradazione lisosomiale della proteina.

È attivo contro diversi ceppi prionici e mostra un potenziale terapeutico superiore ad altre porfirine. Tuttavia, la scarsa penetrazione della barriera emato-encefalica (BBB) limita la sua efficacia in vivo.

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Per superare questo limite, si propongono:

  • Modifiche chimiche per aumentare la penetrazione cerebrale.

  • Nanocarrier per trasporto mirato nel SNC.

  • Terapie combinatorie con antisenso oligonucleotidi (ASO) o altri farmaci che abbassano PrP^C.

The DOXIFF Study and the Potential Protective Effect of Doxycycline

Among the antibiotics analyzed for a possible impact on prion pathogenesis, doxycycline has attracted particular interest. The clinical trial called DOXIFF (DOxIciclina nelle Forme Familiari di CJD) has provided preliminary evidence of the drug's ability to interfere with the accumulation of PrP^Sc.

It is believed that doxycycline can bind to abnormal protein structures, stabilizing their conformation and reducing the formation of toxic aggregates. However, further long-term studies are needed to confirm the therapeutic efficacy and define optimal administration regimens.

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