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The Lengthy and Tortured Historical past of Alpha-Synuclein and Parkinson’s Illness – The Well being Care Weblog


By STEVEN ZECOLA

This examine tracks the decades-long journey to harness alpha-synuclein as a therapy for Parkinson’s illness. Steven Zecola an activist who tracks Parkinson’s analysis and was on THCB final month discussing it, affords three key adjustments wanted to beat the underlying challenges.

A Fast Begin for Alpha-Synuclein R&D

Within the mid-1990’s, Parkinson’s affected person advocacy teams had turn into impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorised for Parkinson’s illness (PD).

The Director of Nationwide Institute of Neurological Problems and Stroke (NINDS) arrange a workshop in August 1995 that featured scientists with experience in human genetics who may open novel avenues for PD analysis.

One such scientist, Robert Nussbaum, made the next remarks on the workshop:

“…discovering genes answerable for familial Parkinson’s needs to be useful for understanding all types of the illness. Methods now accessible ought to enable researchers to seek out the genes answerable for familial Parkinson’s illness in a comparatively brief time.”

Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a serious contributor of irregular clusters of proteins within the mind, not solely in sufferers with synuclein mutations however, extra importantly, in sufferers with sporadic Parkinson’s illness as effectively.

As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union deal with, stated:

“Take into consideration this, your complete retailer of human information now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. It took 9 years. Final 12 months scientists positioned the gene that causes Parkinson’s illness in solely 9 days.”

The NIH is Requested to Take a Management Position

Shortly after President Clinton’s name to motion, a Senate Committee requested the Nationwide Institutes of Well being (NIH) to develop a coordinated effort to reap the benefits of promising alternatives in PD analysis.

In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a serious planning assembly that included all elements of the PD neighborhood. The group’s suggestions fashioned the premise of a five-year PD Analysis Agenda.

The Analysis Agenda was codified in a complete 42-page report that lined all facets of analysis from higher understanding the illness, to creating new analysis capabilities, to growing new therapies, and to enhancing the analysis course of.

Noting the “outstanding paradigm shift in Parkinson’s illness analysis” from the invention of the results of alpha-synuclein, the report said that:

“New insights into the function of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of more practical therapies and supply contemporary analysis alternatives to advance our understanding of Parkinson’s illness”.

NIH invested practically $1 billion from FY 2000 to FY 2004 to implement the PD Analysis Agenda.  A-syn analysis could be funded out of the funds allotted to the classes of Genetics and Epidemiology, with each classes focused to obtain about 15% of the general spending.

Total, there have been 19 broad classes with spending authorizations, together with $32.7 million allotted to Program Administration and Course.

When the PD Analysis Agenda reached the top of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005.  It introduced collectively an industry-wide consortium to evaluate the progress over the earlier 5 years and to develop future instructions for PD analysis.

The members generated greater than fifty particular suggestions.  NIH thought-about these plans and the unmet objectives from earlier efforts and developed a 3-year Plan.

A serious focus of that Plan was to determine and intervene with the causes of PD.

As reiterated within the 2006 Plan:

“…Understanding the function of alpha-synuclein could allow methods to selectively block the dangerous results related to this protein as a novel method to therapy of PD”.

NINDS famous that:

“Whereas PD just isn’t a uncommon or orphan illness, different extra prevalent ailments comparable to stroke, weight problems and diabetes provide significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical corporations have primarily targeted on medicinal chemistry and alterations of current PD or different neurological medication (e.g., dopamine agonists) slightly than investing in new medication.”

In essence, NINDS acknowledged the monetary conundrum of drug improvement for A-syn and different PD therapies, however regarded to academia to unravel the issue by way of its grant program.

Missing success from the efforts of the 2006 Plan, NINDS organized one other convention in January 2014 referred to as: Parkinson’s Illness 2014: Advancing Analysis, Bettering Lives. The aim of this initiative was to determine important challenges and to spotlight the very best priorities for advancing analysis.

Thirty-one suggestions have been offered. The abstract of the convention included the Prime 3 priorities for medical analysis, translational analysis, and primary analysis. Below primary analysis, priorities 1 and a couple of associated to alpha-synuclein.

On condition that the work specified for A-syn analysis was nonetheless at an early stage of primary analysis in 2014, it’s clear that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.

Non-public Pursuits Lastly Transfer Ahead with Alpha-Synuclein

Recognizing the persevering with lack of progress and the necessity for funding, the Michael J. Fox Basis introduced a $10-million “Ken Griffin Alpha-synuclein Imaging Competitors” in 2019 to spur improvement of a vital and elusive imaging analysis instrument for Parkinson’s illness.

In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Common Brigham and Merck— made great developments within the improvement of various alpha-synuclein tracer strategies.

MJFF awarded Merck an extra $1.5 million to proceed the work and convey its instrument to life. The primary-in-human medical trial of its alpha-synuclein PET tracer started in 2023. 

Moreover, after greater than 20 years of primary analysis, 5 non-public analysis corporations filed purposes with the FDA and have initiated early-stage PD trials.

  • Neuropore Therapies and UCB are collaborating on an oral small molecule, which goals to stop the formation of alpha-synuclein clusters.
  • Prothena Biosciences, together with Roche, is testing a humanized anti-alpha-synuclein antibody.
  • Biogen is investigating one other monoclonal antibody towards alpha-synuclein.
  • AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has just lately introduced the acquisition of all of AFFiRiS’ property and underlying mental property associated to its vaccine candidates focusing on a-syn.
  • Vaxxinity makes use of an immunotherapy candidate codenamed UB–312 to focus on poisonous types of aggregated α-synuclein within the mind to combat Parkinson’s. Its Chairman just lately stated that: “Our findings counsel UB-312 might remodel Parkinson’s care, providing hope for improved outcomes with a disease-modifying therapy”.

As with all R&D tasks, there are various remaining challenges within the improvement of A-syn therapies earlier than reaching the market. Nonetheless, assuming that a minimum of one of many 5 on-going trials will likely be profitable, we will anticipate a remedy using A-syn will likely be authorised by the FDA inside the subsequent 5-8 years. The online impact is that the general improvement window between A-syn’s discovery in 1997 and its software to sufferers could be roughly 35 years – assuming that the analysis goes comparatively easily from right here.

Given its efficiency to this point, the view from NIH concerning PD analysis is:

“… Our failures in bringing therapies to the aim line are resulting from remaining massive gaps in information of the underlying biology that causes and drives the illness. As we fill in these gaps, the probabilities of success will improve. A few of the gaps we find out about, others we solely discover out about when the science opens one other door”.

Why Has This Analysis Taken So Lengthy?

With the good thing about hindsight, we will level to 2 areas that accounted for the best obstacles to progress – focus and sources.

In studying the PD analysis plans and reviews from 2000, 2006 and 2014, it seems that NINDS threw every part it knew about PD into the hopper. There have been a whole bunch of suggestions, tasks and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the required abilities, information and pondering means to unravel a finely-honed query.

There merely will not be sufficient nice minds to trace down the entire “to do’s” within the three NINDS PD analysis plans.  Additionally, communications and networking are necessary elements of scientific development, but the aptitude to community with the widespread participation within the small grants program was missing.

The implication of utilizing the time period “focus” is that it comes with the task of accountability and accountability if the precedence doesn’t get executed. There seems to be little exterior oversight of the effectivity and effectiveness of the analysis {dollars} that have been utilized on A-syn or different PD analysis tasks. If something, NIH appears content material with the output.

Lastly, NIH/NINDS knew there was a funding downside in crossing the Valley of Demise from primary analysis to medical trials, however these organizations fell again to their consolation zone, particularly small grants to academicians. This technique didn’t produce the required outcomes.

A Higher Strategy

In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for added funds because the undertaking progressed out of primary analysis and thru the requisite medical trials.

To handle the shortcomings to this point, the Division of Well being and Human Providers (HHS) ought to step in and 1) slim the PD analysis precedence checklist to the highest candidates, 2) require the institution of a strong communications community for sharing data and three) calm down the FDA laws for PD to assist stage the fund-raising taking part in subject.

Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies comparable to A-syn include very excessive dangers and people dangerous funding {dollars} get to decide on between healthcare therapies that undergo 15+ years of primary analysis and costly medical trials and different alternatives that may be launched in lower than a 12 months.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious results on fund-raising. First, the FDA overhang has dried up curiosity in angel and enterprise capital investing in potential therapies comparable to A-syn. The consequence has been a Valley of Demise between primary analysis and drug improvement. Second, even when the preliminary Valley might be crossed by way of authorities grants or non-profit donations, the FDA regulatory scheme places an unlimited burden on corporations to lift scores of tens of millions of {dollars} for prolonged medical trials that face an unsure regulatory consequence.

NIH/NINDS haven’t acknowledged that even with none direct function in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D relies on claims tied to regulatory milestones. Buyers are well-aware of the challenges of the FDA approval course of and it curbs investor curiosity.

Even in primary analysis, the FDA has had a big affect on scientific progress. For the tutorial entrepreneur, early improvement of an efficient regulatory plan might be the distinction between success and failure. Subsequently, regulatory technique turns into a vital element of the innovation course of.

HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome in relation to any proposed adjustments to its processes.

The answer to those challenges, partially, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA needs to be excludedfrom Section 1 and Section 2 trials and from offering any steerage to researchers previous to Section 3 medical trials. Such a change will pace improvement, unleash innovation, and enhance early-stage fund-raising.

Second, to enhance efficiency of the analysis endeavors, NINDS needs to be tasked to develop and handle a proper, hub-and-spoke, communications community amongst all stakeholders concerned in PD analysis. ClinicalTrials.gov doesn’t fulfill this requirement as a result of it accommodates deceptive data.

Facilitating common exchanges of data, information sharing, and collaboration ought to assist to maximise the impression of analysis efforts and keep away from duplication of labor. For the funding neighborhood, a partition within the hub with investment-related data would assist to construct a bridge over the Valley of Demise and convey extra funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications workplace ought to usually be housed by MBAs (slightly than by Ph.D.’s) who’re targeted on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to think about hiring an funding banking agency to help in organising the investor-related element of this data community.

The third advice for change is that NIH ought to convene a really small group of specialists engaged on PD analysis to determine the three most-likely-to-succeed paths to a treatment. It ought to be certain that these paths have enough personnel and enough analysis {dollars} for completion.  Progress needs to be monitored frequently.

Lastly, I ought to point out that the Michael J. Fox Basis has executed a wonderful job on quite a lot of necessary points and needs to be a serious a part of any restructure going ahead. For instance, HHS might outsource the communications hub to MJFF.

The underside line is that every one elements of the PD {industry}, together with the FDA, have to be on the identical web page by way of discovering a treatment for PD inside an inexpensive period of time given current sources whether or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn to this point, and equally, we’ve witnessed that your complete analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.

The Lengthy and Tortured Historical past of Alpha-Synuclein and Parkinson’s Illness

Preface

This examine tracks the decades-long journey to harness alpha-synuclein as a therapy for Parkinson’s illness. The creator affords three key adjustments wanted to beat the underlying challenges.

A Fast Begin for Alpha-Synuclein R&D

Within the mid-1990’s, Parkinson’s affected person advocacy teams had turn into impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorised for Parkinson’s illness (PD).

The Director of Nationwide Institute of Neurological Problems and Stroke (NINDS) arrange a workshop in August 1995 that featured scientists with experience in human genetics who may open novel avenues for PD analysis.

One such scientist, Robert Nussbaum, made the next remarks on the workshop:

“…discovering genes answerable for familial Parkinson’s needs to be useful for understanding all types of the illness. Methods now accessible ought to enable researchers to seek out the genes answerable for familial Parkinson’s illness in a comparatively brief time.”

Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a serious contributor of irregular clusters of proteins within the mind, not solely in sufferers with synuclein mutations however, extra importantly, in sufferers with sporadic Parkinson’s illness as effectively.

As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union deal with, stated:

“Take into consideration this, your complete retailer of human information now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. It took 9 years. Final 12 months scientists positioned the gene that causes Parkinson’s illness in solely 9 days.”

The NIH is Requested to Take a Management Position

Shortly after President Clinton’s name to motion, a Senate Committee requested the Nationwide Institutes of Well being (NIH) to develop a coordinated effort to reap the benefits of promising alternatives in PD analysis.

In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a serious planning assembly that included all elements of the PD neighborhood. The group’s suggestions fashioned the premise of a five-year PD Analysis Agenda.

The Analysis Agenda was codified in a complete 42-page report that lined all facets of analysis from higher understanding the illness, to creating new analysis capabilities, to growing new therapies, and to enhancing the analysis course of.

Noting the “outstanding paradigm shift in Parkinson’s illness analysis” from the invention of the results of alpha-synuclein, the report said that:

“New insights into the function of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of more practical therapies and supply contemporary analysis alternatives to advance our understanding of Parkinson’s illness”.

NIH invested practically $1 billion from FY 2000 to FY 2004 to implement the PD Analysis Agenda.  A-syn analysis could be funded out of the funds allotted to the classes of Genetics and Epidemiology, with each classes focused to obtain about 15% of the general spending.

Total, there have been 19 broad classes with spending authorizations, together with $32.7 million allotted to Program Administration and Course.

When the PD Analysis Agenda reached the top of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005.  It introduced collectively an industry-wide consortium to evaluate the progress over the earlier 5 years and to develop future instructions for PD analysis.

The members generated greater than fifty particular suggestions.  NIH thought-about these plans and the unmet objectives from earlier efforts and developed a 3-year Plan.

A serious focus of that Plan was to determine and intervene with the causes of PD. As reiterated within the 2006 Plan:

“…Understanding the function of alpha-synuclein could allow methods to selectively block the dangerous results related to this protein as a novel method to therapy of PD”.

NINDS famous that:

“Whereas PD just isn’t a uncommon or orphan illness, different extra prevalent ailments comparable to stroke, weight problems and diabetes provide significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical corporations have primarily targeted on medicinal chemistry and alterations of current PD or different neurological medication (e.g., dopamine agonists) slightly than investing in new medication.”

In essence, NINDS acknowledged the monetary conundrum of drug improvement for A-syn and different PD therapies, however regarded to academia to unravel the issue by way of its grant program.

Missing success from the efforts of the 2006 Plan, NINDS organized one other convention in January 2014 referred to as: Parkinson’s Illness 2014: Advancing Analysis, Bettering Lives. The aim of this initiative was to determine important challenges and to spotlight the very best priorities for advancing analysis.

Thirty-one suggestions have been offered. The abstract of the convention included the Prime 3 priorities for medical analysis, translational analysis, and primary analysis. Below primary analysis, priorities 1 and a couple of associated to alpha-synuclein.

On condition that the work specified for A-syn analysis was nonetheless at an early stage of primary analysis in 2014, it’s clear that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.

Non-public Pursuits Lastly Transfer Ahead with Alpha-Synuclein

Recognizing the persevering with lack of progress and the necessity for funding, the Michael J. Fox Basis introduced a $10-million “Ken Griffin Alpha-synuclein Imaging Competitors” in 2019 to spur improvement of a vital and elusive imaging analysis instrument for Parkinson’s illness.

In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Common Brigham and Merck— made great developments within the improvement of various alpha-synuclein tracer strategies.

MJFF awarded Merck an extra $1.5 million to proceed the work and convey its instrument to life. The primary-in-human medical trial of its alpha-synuclein PET tracer started in 2023. 

Moreover, after greater than 20 years of primary analysis, 5 non-public analysis corporations filed purposes with the FDA and have initiated early-stage PD trials.

  • Neuropore Therapies and UCB are collaborating on an oral small molecule, which goals to stop the formation of alpha-synuclein clusters.
  • Prothena Biosciences, together with Roche, is testing a humanized anti-alpha-synuclein antibody.
  • Biogen is investigating one other monoclonal antibody towards alpha-synuclein.
  • AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has just lately introduced the acquisition of all of AFFiRiS’ property and underlying mental property associated to its vaccine candidates focusing on a-syn.
  • Vaxxinity makes use of an immunotherapy candidate codenamed UB–312 to focus on poisonous types of aggregated α-synuclein within the mind to combat Parkinson’s. Its Chairman just lately stated that: “Our findings counsel UB-312 might remodel Parkinson’s care, providing hope for improved outcomes with a disease-modifying therapy”.

As with all R&D tasks, there are various remaining challenges within the improvement of A-syn therapies earlier than reaching the market. Nonetheless, assuming that a minimum of one of many 5 on-going trials will likely be profitable, we will anticipate a remedy using A-syn will likely be authorised by the FDA inside the subsequent 5-8 years. The online impact is that the general improvement window between A-syn’s discovery in 1997 and its software to sufferers could be roughly 35 years – assuming that the analysis goes comparatively easily from right here.

Given its efficiency to this point, the view from NIH concerning PD analysis is:

“… Our failures in bringing therapies to the aim line are resulting from remaining massive gaps in information of the underlying biology that causes and drives the illness. As we fill in these gaps, the probabilities of success will improve. A few of the gaps we find out about, others we solely discover out about when the science opens one other door”.

Why Has This Analysis Taken So Lengthy?

With the good thing about hindsight, we will level to 2 areas that accounted for the best obstacles to progress – focus and sources.

In studying the PD analysis plans and reviews from 2000, 2006 and 2014, it seems that NINDS threw every part it knew about PD into the hopper. There have been a whole bunch of suggestions, tasks and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the required abilities, information and pondering means to unravel a finely-honed query.

There merely will not be sufficient nice minds to trace down the entire “to do’s” within the three NINDS PD analysis plans.  Additionally, communications and networking are necessary elements of scientific development, but the aptitude to community with the widespread participation within the small grants program was missing.

The implication of utilizing the time period “focus” is that it comes with the task of accountability and accountability if the precedence doesn’t get executed. There seems to be little exterior oversight of the effectivity and effectiveness of the analysis {dollars} that have been utilized on A-syn or different PD analysis tasks. If something, NIH appears content material with the output.

Lastly, NIH/NINDS knew there was a funding downside in crossing the Valley of Demise from primary analysis to medical trials, however these organizations fell again to their consolation zone, particularly small grants to academicians. This technique didn’t produce the required outcomes.

A Higher Strategy

In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for added funds because the undertaking progressed out of primary analysis and thru the requisite medical trials.

To handle the shortcomings to this point, the Division of Well being and Human Providers (HHS) ought to step in and 1) slim the PD analysis precedence checklist to the highest candidates, 2) require the institution of a strong communications community for sharing data and three) calm down the FDA laws for PD to assist stage the fund-raising taking part in subject.

Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies comparable to A-syn include very excessive dangers and people dangerous funding {dollars} get to decide on between healthcare therapies that undergo 15+ years of primary analysis and costly medical trials and different alternatives that may be launched in lower than a 12 months.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious results on fund-raising. First, the FDA overhang has dried up curiosity in angel and enterprise capital investing in potential therapies comparable to A-syn. The consequence has been a Valley of Demise between primary analysis and drug improvement. Second, even when the preliminary Valley might be crossed by way of authorities grants or non-profit donations, the FDA regulatory scheme places an unlimited burden on corporations to lift scores of tens of millions of {dollars} for prolonged medical trials that face an unsure regulatory consequence.

NIH/NINDS haven’t acknowledged that even with none direct function in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D relies on claims tied to regulatory milestones. Buyers are well-aware of the challenges of the FDA approval course of and it curbs investor curiosity.

Even in primary analysis, the FDA has had a big affect on scientific progress. For the tutorial entrepreneur, early improvement of an efficient regulatory plan might be the distinction between success and failure. Subsequently, regulatory technique turns into a vital element of the innovation course of.

HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome in relation to any proposed adjustments to its processes.

The answer to those challenges, partially, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA needs to be excludedfrom Section 1 and Section 2 trials and from offering any steerage to researchers previous to Section 3 medical trials. Such a change will pace improvement, unleash innovation, and enhance early-stage fund-raising.

Second, to enhance efficiency of the analysis endeavors, NINDS needs to be tasked to develop and handle a proper, hub-and-spoke, communications community amongst all stakeholders concerned in PD analysis. ClinicalTrials.gov doesn’t fulfill this requirement as a result of it accommodates deceptive data.

Facilitating common exchanges of data, information sharing, and collaboration ought to assist to maximise the impression of analysis efforts and keep away from duplication of labor. For the funding neighborhood, a partition within the hub with investment-related data would assist to construct a bridge over the Valley of Demise and convey extra funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications workplace ought to usually be housed by MBAs (slightly than by Ph.D.’s) who’re targeted on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to think about hiring an funding banking agency to help in organising the investor-related element of this data community.

The third advice for change is that NIH ought to convene a really small group of specialists engaged on PD analysis to determine the three most-likely-to-succeed paths to a treatment. It ought to be certain that these paths have enough personnel and enough analysis {dollars} for completion.  Progress needs to be monitored frequently.

Lastly, I ought to point out that the Michael J. Fox Basis has executed a wonderful job on quite a lot of necessary points and needs to be a serious a part of any restructure going ahead. For instance, HHS might outsource the communications hub to MJFF.

The underside line is that every one elements of the PD {industry}, together with the FDA, have to be on the identical web page by way of discovering a treatment for PD inside an inexpensive period of time given current sources whether or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn to this point, and equally, we’ve witnessed that your complete analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.

Steve Zecola bought his internet software and internet hosting enterprise when he was recognized with Parkinson’s illness twenty three years in the past.  Since then, he has run a consulting follow, taught in graduate enterprise faculty, and exercised extensively

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