MJFF recently hosted a Summit to discuss the translation of
alpha-synuclein discoveries into meaningful therapies for patients.
Below are some takeaways from the discussion.
Discussion of Alpha-Synuclein as a Therapeutic Target
Jennifer Johnston (Elan)
moderated a lively discussion around the questions related to alpha-synuclein
as a target for drug discovery and development. (View Dr. Johnston's slides here.) There were several relevant
questions that surfaced from the discussion that still have yet to be
adequately answered experimentally:
1. What
is the toxic species of alpha-synuclein?
MJFF attempted
to address this question with the 2007 Critical Challenges RFA that solicited
applications to experimentally determine which species of alpha-synuclein
(phosphorylated, truncated, dimerized/oligomerized/fibrillized, etc ) is the
relevant target against which drugs should be designed. Despite several
publications in model organisms and rodents examining this question there is
yet to be a consensus. However, everyone in the room agreed lowering levels of alpha-synuclein is
the most well validated approach due to the genetic evidence in
families with duplication and triplication of the alpha-synuclein gene and the
data demonstrating cellular alpha-synuclein levels accumulate with aging prior
to inclusion formation.
2. What
is the normal function of Alpha-synuclein?
Since the normal
function of alpha-synuclein is still unknown, alpha-synuclein as a target is still
in question; in other words one does not know what effect lowering
alpha-synuclein levels will have on normal cellular processes. Thus the
consensus was that we should aim to lower levels back to “normal” rather than
knocking it down completely. It was acknowledged that most current techniques
(ie, siRNA) cannot completely knock down expression, perhaps avoiding this
issue.
3. What
is an inclusion?
There seemed to be
confusion in the room about the terminology of alpha-synuclein species. The
group felt it may be beneficial for the field to develop consensus definitions
of the various forms of alpha-synuclein such as fibril, inclusion, oligomer,
and Lewy body. The group felt these terms are often used interchangeably and
there is inconsistency from investigator to investigator on the terminology. If
the field were able to better define these species perhaps we would have more
consistent comparison of experiments published in the literature.
What is needed in a preclinical dataset to move forward an alpha-synuclein
based therapy?
Warren Hirst (Pfizer)
moderated a discussion over what the preclinical package would look like for an
alpha-synuclein based therapy. (View Dr. Hirst's slides here.) He pointed towards some minimal requirements
that industry would feel comfortable with: efficacy in a cell-based model of
alpha-synuclein toxicity/dysfunction, evidence that the drug actually engages
the target and affects alpha-synuclein in animals, and some functional endpoint
in animals that is directly related to alpha-synuclein function.
Key Discussion Question: Does one need to observe a dopamine and/or
motor improvement in a rodent model to trigger further development of an
alpha-synuclein based therapeutic?
Outcome: A paradigm shift seemed to
occur in the attendees’ opinion not observed before in previous alpha-synuclein
discussions. Given the paucity of alpha-synuclein based rodent models that
demonstrate a consistent and reproducible dopaminergic and/or motor deficit,
the group conceded that one need not observe an improvement in a motor or
dopaminergic phenotype with drug administration. The group seemed to believe that if one had a pathological endpoint
(such as an effect on alpha-synuclein inclusions or total alpha-synuclein
levels) in combination with improvement in a functional outcome that is
directly related to alpha-synuclein expression (olfaction, constipation, etc),
this would be sufficient to justify further IND enabling studies.
Key Discussion Question: What cell based assays are most
appropriate for screening compounds against alpha-synuclein?
Outcome: There was no consensus on the “best” assay to
utilize. However a number of relevant issues were discussed. First, some
wondered whether a model of alpha-synuclein-induced toxicity (cells, yeast,
etc) was the most appropriate since it wasn’t clear what the mechanism of
toxicity was other than over-expression of alpha-synuclein. However, this does
imitate the “human model” of genetic duplication/triplication of
alpha-synuclein. The participants discussed other, perhaps more nuanced, models
of alpha-synuclein such as axonal transport, cytoskeletal dysfunction, etc.
What will the first alpha-synuclein based therapeutic look like?
Franz Hefti (Avid) moderated a fascinating
discussion of how one would approach a proof of concept clinical trial for an
alpha-synuclein based therapeutic. (View Dr. Hefti's slides here.) He provided his interpretation of a talk by
Russel Katz from the Food and Drug Administration at the December 2009 World
Federation of Neurology (WFN) Congress on Parkinson’s disease and Related Disorders.
The take-home message was that in the current environment with existing
clinical scales and biomarkers, in order to achieve a disease modification
label in Parkinson’s disease, one would need to demonstrate an improvement in
both the clinical symptoms and an improvement in a biomarker associated with a
disease modifying mechanism. Thus, there was considerable discussion of the
current approach to the Alzheimer’s clinical trials in which sponsors are
collecting both clinical data in addition to beta amyloid imaging and CSF
biomarkers.
The key outcome of the
clinical trial discussion was the need to develop alpha-synuclein based
biomarkers including imaging (MJFF is supporting multiple groups on this
approach) and biochemical markers (CSF and blood biomarkers). Additionally, the
group thought it would be useful to examine existing biochemical biomarkers in
the current transgenic animal models to determine whether they may change with
introduction of a therapeutic.
MJFF recently hosted a Summit to discuss the translation of alpha-synuclein discoveries into meaningful therapies for patients. Below are some takeaways from the discussion.
Discussion of Alpha-Synuclein as a Therapeutic Target
Jennifer Johnston (Elan) moderated a lively discussion around the questions related to alpha-synuclein as a target for drug discovery and development. (View Dr. Johnston's slides here.) There were several relevant questions that surfaced from the discussion that still have yet to be adequately answered experimentally:
1. What is the toxic species of alpha-synuclein?
MJFF attempted to address this question with the 2007 Critical Challenges RFA that solicited applications to experimentally determine which species of alpha-synuclein (phosphorylated, truncated, dimerized/oligomerized/fibrillized, etc ) is the relevant target against which drugs should be designed. Despite several publications in model organisms and rodents examining this question there is yet to be a consensus. However, everyone in the room agreed lowering levels of alpha-synuclein is the most well validated approach due to the genetic evidence in families with duplication and triplication of the alpha-synuclein gene and the data demonstrating cellular alpha-synuclein levels accumulate with aging prior to inclusion formation.
2. What is the normal function of Alpha-synuclein?
Since the normal function of alpha-synuclein is still unknown, alpha-synuclein as a target is still in question; in other words one does not know what effect lowering alpha-synuclein levels will have on normal cellular processes. Thus the consensus was that we should aim to lower levels back to “normal” rather than knocking it down completely. It was acknowledged that most current techniques (ie, siRNA) cannot completely knock down expression, perhaps avoiding this issue.
3. What is an inclusion?
There seemed to be confusion in the room about the terminology of alpha-synuclein species. The group felt it may be beneficial for the field to develop consensus definitions of the various forms of alpha-synuclein such as fibril, inclusion, oligomer, and Lewy body. The group felt these terms are often used interchangeably and there is inconsistency from investigator to investigator on the terminology. If the field were able to better define these species perhaps we would have more consistent comparison of experiments published in the literature.
What is needed in a preclinical dataset to move forward an alpha-synuclein based therapy?
Warren Hirst (Pfizer) moderated a discussion over what the preclinical package would look like for an alpha-synuclein based therapy. (View Dr. Hirst's slides here.) He pointed towards some minimal requirements that industry would feel comfortable with: efficacy in a cell-based model of alpha-synuclein toxicity/dysfunction, evidence that the drug actually engages the target and affects alpha-synuclein in animals, and some functional endpoint in animals that is directly related to alpha-synuclein function.
Key Discussion Question: Does one need to observe a dopamine and/or motor improvement in a rodent model to trigger further development of an alpha-synuclein based therapeutic?
Outcome: A paradigm shift seemed to occur in the attendees’ opinion not observed before in previous alpha-synuclein discussions. Given the paucity of alpha-synuclein based rodent models that demonstrate a consistent and reproducible dopaminergic and/or motor deficit, the group conceded that one need not observe an improvement in a motor or dopaminergic phenotype with drug administration. The group seemed to believe that if one had a pathological endpoint (such as an effect on alpha-synuclein inclusions or total alpha-synuclein levels) in combination with improvement in a functional outcome that is directly related to alpha-synuclein expression (olfaction, constipation, etc), this would be sufficient to justify further IND enabling studies.
Key Discussion Question: What cell based assays are most appropriate for screening compounds against alpha-synuclein?
Outcome: There was no consensus on the “best” assay to utilize. However a number of relevant issues were discussed. First, some wondered whether a model of alpha-synuclein-induced toxicity (cells, yeast, etc) was the most appropriate since it wasn’t clear what the mechanism of toxicity was other than over-expression of alpha-synuclein. However, this does imitate the “human model” of genetic duplication/triplication of alpha-synuclein. The participants discussed other, perhaps more nuanced, models of alpha-synuclein such as axonal transport, cytoskeletal dysfunction, etc.
What will the first alpha-synuclein based therapeutic look like?
Franz Hefti (Avid) moderated a fascinating discussion of how one would approach a proof of concept clinical trial for an alpha-synuclein based therapeutic. (View Dr. Hefti's slides here.) He provided his interpretation of a talk by Russel Katz from the Food and Drug Administration at the December 2009 World Federation of Neurology (WFN) Congress on Parkinson’s disease and Related Disorders. The take-home message was that in the current environment with existing clinical scales and biomarkers, in order to achieve a disease modification label in Parkinson’s disease, one would need to demonstrate an improvement in both the clinical symptoms and an improvement in a biomarker associated with a disease modifying mechanism. Thus, there was considerable discussion of the current approach to the Alzheimer’s clinical trials in which sponsors are collecting both clinical data in addition to beta amyloid imaging and CSF biomarkers.
The key outcome of the clinical trial discussion was the need to develop alpha-synuclein based biomarkers including imaging (MJFF is supporting multiple groups on this approach) and biochemical markers (CSF and blood biomarkers). Additionally, the group thought it would be useful to examine existing biochemical biomarkers in the current transgenic animal models to determine whether they may change with introduction of a therapeutic.