Tag: Steven Zecola

The Long and Tortured History of Alpha-Synuclein and Parkinson’s Disease

Mar 29, 2024

By STEVEN ZECOLA

This study tracks the decades-long journey to harness alpha-synuclein as a treatment for Parkinson’s disease. Steven Zecola an activist who tracks Parkinson’s research and was on THCB last month discussing it, offers three key changes needed to overcome the underlying challenges.

A Quick Start for Alpha-Synuclein R&D

In the mid-1990’s, Parkinson’s patient advocacy groups had become impatient by the absence of any major therapeutic advances in the 25 years since L-dopa had been approved for Parkinson’s disease (PD).

The Director of National Institute of Neurological Disorders and Stroke (NINDS) set up a workshop in August 1995 that featured scientists with expertise in human genetics who might open novel avenues for PD research.

One such scientist, Robert Nussbaum, made the following remarks at the workshop:

“…finding genes responsible for familial Parkinson’s should be helpful for understanding all forms of the disease. Techniques now available should allow researchers to find the genes responsible for familial Parkinson’s disease in a relatively short time.”

Two years later in 1997, Spillantini et al. showed that alpha-synuclein (A-syn) was a major contributor of abnormal clusters of proteins in the brain, not only in patients with synuclein mutations but, more importantly, in patients with sporadic Parkinson’s disease as well.

As Nussbaum had predicted, progress had occurred rapidly. President Clinton in his 1998 State of the Union address, said:

“Think about this, the entire store of human knowledge now doubles every 5 years. In the 1980’s, scientists identified the gene causing cystic fibrosis. It took 9 years. Last year scientists located the gene that causes Parkinson’s disease in only 9 days.”

The NIH is Asked to Take a Leadership Role

Shortly after President Clinton’s call to action, a Senate Committee asked the National Institutes of Health (NIH) to develop a coordinated effort to take advantage of promising opportunities in PD research.

In response, the NIH and the National Institute of Neurological Disease and Stroke (NINDS) held a major planning meeting that included all components of the PD community. The group’s recommendations formed the basis of a five-year PD Research Agenda.

The Research Agenda was codified in a comprehensive 42-page report that covered all aspects of research from better understanding the disease, to creating new research capabilities, to developing new treatments, and to enhancing the research process.

Noting the “remarkable paradigm shift in Parkinson’s disease research” from the discovery of the effects of alpha-synuclein, the report stated that:

“New insights into the role of synucleins in the pathobiology of Parkinson’s disease would accelerate discovery of more effective therapies and provide fresh research opportunities to advance our understanding of Parkinson’s disease”.

NIH invested nearly $1 billion from FY 2000 to FY 2004 to implement the PD Research Agenda. A-syn research would be funded out of the funds allocated to the categories of Genetics and Epidemiology, with both categories targeted to receive about 15% of the overall spending.

Overall, there were 19 broad categories with spending authorizations, including $32.7 million allocated to Program Management and Direction.

When the PD Research Agenda reached the end of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005. It brought together an industry-wide consortium to assess the progress over the previous five years and to develop future directions for PD research.

The participants generated more than fifty specific recommendations. NIH considered these plans and the unmet goals from previous efforts and developed a 3-year Plan.

A major focus of that Plan was to identify and intervene with the causes of PD.

The FDA’s Culture: Should Safety Dominate All Practices?

Aug 26, 2021

By STEVEN ZECOLA

An organization’s culture is an internal set of shared values, attitudes and practices. The cohesiveness of the organizational culture will affect whether the entity will meet its vision, purpose, and goals.

One type of organizational culture is hierarchical in nature. Unlike a risk-taking culture, this structure features policy, process and precision. It is best suited for mature and stable organizations.

The disadvantage of a hierarchal culture is that its stability and control can turn into rigidity. In many cases, the organization develops a negative attitude towards ideas supplied by third parties. It paints itself as having the perfect answer for every issue, no matter how large or small.

My interactions with the FDA suggest that its cultural practices are focused on safety, seemingly to the exclusion of all other issues. This practice may be appropriate in the regulation of food, but not for drug research where flexibility and creativity are required to cure complex diseases.

Over the past decade, I have witnessed an excessive adherence to its existing practices in the context of BRCA1-related breast cancer, metastatic cancer, precision medicines, “Big Data” and Parkinson’s disease. While the rulings were directed at me, the FDA’s position on these issues has impacted millions of people for the worse.

The Case to Realign Parkinson’s Disease Research

Jul 15, 2021

By STEVEN ZECOLA

If asked, the leaders of the research organizations working on Parkinson’s disease would say that they have made tremendous progress and are optimistic on finding a cure for the disease.

In truth, this viewpoint understates the magnitude of the challenge and results in insufficient resources being devoted to PD. Given the size of the challenge versus the available resources, most research studies today don’t even include finding a cure for PD as part of their objective.

The time is ripe to get everybody on the same page when it comes to the objectives, resources, and timelines for PD research.

What We Know About Parkinson’s Disease

Parkinson’s disease (PD) is a chronic, progressive movement disorder that affects the lives of almost one million Americans. Roughly 50,000 of the inflicted people die each year, often by injuries from falling. The incidence of PD is expected to expand to 1.6 million in the U.S. by the year 2037.

The characteristic motor symptoms of PD are tremors, stiffness, slowed movement and impaired balance. Over time, people with PD also experience non-motor symptoms including changes in mood, problems with attention and memory, sleep disturbances, fatigue, and changes in bowel and bladder function. PD has a considerable impact on the quality of life.

The cost to treat PD has been estimated to be $50 billion a year, split equally between the direct cost of care and the indirect costs of lost opportunities for the patients and caregivers.

PD is a complex disease which is thought to result from an interaction between genetic and environmental risk factors. More than 20 genes have been identified as having an impact on the onset of PD. However, genetic variation is estimated to contribute only about 25% to the overall risk of developing PD. Moreover, like the majority of neurodegenerative disorders, little insight is available on how specific sequence variations contribute to disease development and progression.

In short, the exact cause of PD is unknown. However, we know that that there is more than one manifestation of the disease. We can also reasonably conclude that more than one single element or therapy will be required to cure the disease.

What We Know About Parkinson’s Disease Research

PD was first discovered and described by James Parkinson in 1817 in London, England.

In 1911, the efforts of Kazimierz Funk, a Polish biochemist, paid off with the identification of Levodopa as a potential treatment.

By 1970, the FDA approved the use of Levodopa combined with Carbidopa for the treatment of PD. Since then, this combination has remained the gold standard for treatment.

During the last 50 years, many attempts have been made to improve this treatment and avoid its long-term complications. While several enhancements have been approved by the FDA and have helped patients, no treatment has cured or slowed the progression of the disease.

21st Century Cures Act: Away From the “Valley of Death”

Dec 31, 2015

By STEVEN ZECOLA

Most people would agree that the number of cures for debilitating and costly illnesses such as Alzheimer’s disease, Parkinson’s disease and cancer have been too few and far between.

To address this issue, the U.S. House of Representatives recently passed the 21st Century Cures Act, which now resides in the U.S. Senate for action. The main thrusts of the Act are to increase government funding for research and to improve several regulatory processes.

Unfortunately, the Act does not address the root cause of the dearth of cures; namely, the inhospitable investment climate for research and development (“R&D”) culminating in the “Valley of Death” for most health-related discoveries.