Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CureCN (Adeno-Associated Virus Vector-Mediated Liver Gene Therapy for Crigler-Najjar Syndrome)

Teaser

The CureCN project aims to develop a curative gene therapy against the ultra-rare Crigler-Najjar syndrome (CN). CN is a life-threatening liver disease which affects one in a million individuals at birth. It is caused by the deficiency of a liver-specific enzyme (uridine...

Summary

The CureCN project aims to develop a curative gene therapy against the ultra-rare Crigler-Najjar syndrome (CN). CN is a life-threatening liver disease which affects one in a million individuals at birth.
It is caused by the deficiency of a liver-specific enzyme (uridine diphosphate Glucuronosyltransferase 1A1) that leads to the accumulation of toxic unconjugated bilirubin in all body tissues. Untreated, CN causes irreversible neurological damage in the brain and leads to death. The only curative treatment currently available is a liver transplant that implies high risks of complications.
Treatment with phototherapy – a treatment with blue light – reduces symptoms, but is very debilitating as it requires 10 to 14 hours therapy per day. Furthermore, it loses its efficacy over time so that all patients depend upon a liver transplant in the long term. On the other hand, phototherapy does not eliminate the risk of life-threatening spikes of bilirubin. The lack of a permanent curative treatment of CN results in a shortened life expectancy of the affected patients. The goal of the CureCN consortium is thus to prove the safety and efficacy of an adeno-associated virus (AVV) gene therapy in a clinical trial and make it available to patients.
The project’s major objectives are to :
- Develop a curative AAV gene therapy and validating a technology transposable to many other inherited liver-related disorders
- Prove the safety and efficacy of the vector-mediated gene transfer with AAV in a clinical trial
- Provide a treatment suitable for very young CN patients as well as for older patients with a pre-existing immunity to AAV
- Verify a way to eradicate pre-existing immunity to AAV
- Accelerate the orphan drug development towards a marketing authorisation for the treatment
- Establish the first global CN patient registry.
Overall, CureCN wants to provide better information for patients, families, healthcare providers and the general public about CN syndrome and existing treatments.

Work performed

During the first Period of the project, the CureCN partners have taken significant initial steps toward the realization of the goals of the research program.
These initial steps consisted in starting the manufacturing of GMP lots of AAV vector that can be used to treat the participants in the 2 first cohorts of the clinical trial. Additionally, to anticipate the validation of the production process, a potency assay was developed, and is ready to be validated.
Four clinical sites have received the approvals from the competent Authorities to initiate the enrolment in the clinical trial.-First subject was included on May 2018, and was dosed with Investigational Medicinal Product (IMP) on December 2018. Four other subjects are currently enrolled in the trial in the baseline observation period that precedes IMP administration.
A world registry of CN patients was created. Data were collected from a pool of about 200 patients; a first analysis revealed the lethality of the disease when availability of the treatment is limited. Furthermore, contacts have been established with patients and or families from 17 countries over 5 continents.
Preclinical work in animal models of CN syndrome has also started to determine the safety and efficacy of gene transfer in neonate and juvenile animals, to support the Pediatric Investigational Plan for the investigational gene therapy.
CureCN also aims at addressing fundamental limiting issues associated to the AAV vector technology. In particular, development of persisting, high-titer anti-AAV neutralizing antibodies (NAbs) after vector infusion prevent vector re-administration. This precludes enrolment of very young children in the trial, as long-term therapeutic efficacy after a single vector administration is not expected in these patients due to vector genome dilution. Additionally, because of exposure to the wild-type virus, a large proportion of humans are positive for anti-AAV Nabs, thus ineligible for enrolment in AAV-mediated gene transfer trials.
To this aim, preclinical work aimed at assessing the safety and efficacy of the combination of immunosuppression with the investigational drug has started in preclinical models of CN syndrome. Experiments in CN rats were performed in which the IMP was administered with rapamycin alone or in combination with prednisolone.
The CureCN proposal aims at developing novel technologies for the modulation of antibody responses directed against AAV vectors, and for the physical removal of pre-existing antibodies to AAV from the bloodstream. Therefore, the expected technological innovation derived from the studies conducted in the frame of this proposal will have a major impact on the development of all AAV-based gene therapies for inherited diseases requiring systemic vector administration.
Several experiments were performed with a prototype plasmapheresis column specific for the elimination of anti-AAV antibodies from the circulation. In parallel, molecularly imprinted polymers (MIP) with high affinity for anti-AAV antibodies were developed. A series of potential binding epitopes were identified using anti-AAV antibodies purified from large pools of human IgG, these will be the bases for the development of MIPs that will be used in a plasmapheresis column. Currently, testing of the ability of these epitope to act as decoys and protect AAV vectors from neutralization is ongoing in a series of experiments in vitro and in vivo.
The development of a novel therapeutic approach, with concrete benefits for people living with severe CN syndrome is expected to have an impact on their quality of life: the ability of AAV vector gene therapy will allow patients to reduce or eliminate phototherapy.
The gene therapy vector developed by CureCN is ideally and uniquely designed to ensure the safe and effective expression of the transgene both in adult and paediatric CN patients. The CureCN network have hardly any equals in the field of development of new therapies for

Final results

One of the main limitations of all gene therapies based on AAV vectors aimed at treating paediatric indications is the persistence of the transgene expression. Vector re-administration is currently not feasible, due to the high immunogenicity of the AAV vectors. CureCN will implement a new disruptive technology, which has the potential to revolutionise the entire field of AAV gene therapy, by changing the modality of the treatment from “once in life” to “on demand based on therapeutic need”.
Pre-existing immunity to AAV is a major limitation to the scope of in vivo gene therapies in humans, as it prevents up to 60% of patients from receiving AAV vector administration. CureCN aims at developing a new technology that, if successful, can be broadly implemented in gene therapy trials to treat eligible patients, regardless their serology status.
The availability of a curative treatment for all CN patients, including very young children will change dramatically the way the disease is managed. An effective treatment will prevent irreversible brain damage caused by bilirubin spikes during trauma / illness occurring during childhood and adolescence in CN patients treated with phototherapy. Devising safe and reliable strategies are addressed for the early treatment of children affected by the disease.

Website & more info

More info: https://curecn.eu/.