(Dr. Joutel and Pr. Chabriat) The initial step, prior
to phase 1, in evaluating an hypothesis of treatment strategy is to evaluate
the potential drug on animals. This process includes verifying its
effectiveness, defining mechanisms of action of the treatment, determining
biomarkers as proof-of-concept and tools permitting to measure and monitor
the effect of the tested drug. It is also necessary to evaluate the toxicity
of the treatment, generally in two different animal species. For these
toxicity tests, the drug must be produced in sufficiently large quantities
under very controlled conditions. Such a stage would last about five years.
If we would manage to pass this animal stage with antibodies testing, the
clinical phase could be faster compared to other drugs because there are
already a lot of data on this component. In humans, phase 1 lasts about a
year and a half. We first study reactions in healthy subjects.
Phase 2’s goal is to assess dosage of the drug as well
as potential tolerance and toxicity. The group of people participating in
the test receives different dosages in order to identify which one is the
most effective with no side effects.
Phase 3 is used to test effectiveness based on clinical
criteria or markers of effect assessment e.g. MRI. These last two steps
require a few years, in general, based on number of participants. For a test
to have high probability of success, we must be able to prove it: we must
take precautions to properly select the composition of the treatment sample,
select participants at an age and stage of disease corresponding well to the
target mechanism of the treatment, have identified and validated markers so
that the effect can be validated and measured.
It is better not to rush in order to make sure that the
strategy is good in humans. In the case of the NOTCH3 antibodies strategy
currently under CADASIL evaluation, it is very important to validate its
effectiveness in several mouse models, and to try developing evaluation
methods transposable to humans, in order to minimize the risk of failure.
It is also important to understand the mechanism of
action of the treatment and to have established a method to measure its
impact. It will cost several million euros to arrive at a treatment. The
support of an association is critical to collect donations and grants.
Projects on therapeutic tools to prevent or delay effects of CADASIL disease
are complemented by other research work on finding ways to care for and
improve conditions of patients who are already experiencing problems related
to the disease. A Chinese post-doctorate researcher has just joined Pr.
Chabriat ’s team in a program of cooperation between the Chinese and French
Academies of Sciences, as well as thanks to a grant from ARNEVA (Association
for Neuro-Vascular Research at Lariboisière Hospital). He will lead a study
on blood pressure of arteries.
We will study its role in the disease and the
occurrence of new small infarcts, using MRI. It might be possible to
intervene early enough if we could evaluate pressure variation indexes that
are associated with the occurrence of strokes. It is also important to help
patients recover from a succession of strokes and improve rehab of
functional state (General Assembly, France 2016)