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Below is the full transcript of KIF1A.ORG’s “Overview of Therapeutic Development Strategy” video. You can translate the text by using our website’s Google translator.

Video 1: Overview of Therapeutic Development Strategy:

Hi everyone, my name is Dr. Dominique Lessard. I am the Chief Science Officer at KIF1A.ORG. I joined the org full time a year ago and in the year that I have been involved, we have had a LOT of advancements and developments regarding our therapeutic strategy for treating and finding a cure for KIF1A Associated Neurological Disorder (KAND).

All of us at the org want to make sure that you, our community, are informed and play an integral role in this process of therapeutic development. Therefore, we will be creating a series of videos to update you all on our 2021 therapeutic development strategy and open a dialog about this process, answer any questions, etc.

This first video is going to serve an as overview of KIF1A.ORGs therapeutic development strategy covering the basics of how we operate as an org, the logic that drives therapeutic action and researcher and important considerations about risk and how we define failure and success.

First, let’s provide a little bit of background about our team.

The important point that I want to make in going over our team is that every one of our team members plays a highly important role in our therapeutic development process. Be it helping make connections, facilitating conversations, handling financials, etc., our success relies on our team functioning as a well-oiled machine… which we do quite well! We all bring our own personal strengths and weaknesses to the table, and they all balance each other out in a way that allows us to work very efficiently.

While we have our internal team, we also collaborate and work with a number of external team members in the form of researchers, clinicians and experts in therapeutic development that are crucial in moving our therapeutic development forward. This slide highlights just a few members of our growing research which we will discuss later on. You’ll find some long-term KIF1A champions like Dr. Wendy Chung and Lia Boyle, Dr. Cat Lutz, and Hans Christinger, as well as some newer champions that have recently jumped on board. All of these team members bring a unique and highly-skilled knowledge base that we lean to make informed, science-driven decisions about our therapeutic strategy.

Now that we know a bit more about our team, let’s talk about how our team drives therapeutic development.

In discussing the ways that KIF1A.ORG drives therapeutic development forward, there are a number of different efforts and initiatives that come to mind.

First, we intentionally cast a wide network of opportunities. While it is important to be focused in our therapeutic development efforts, it is also equally at important to not be so focused in on a specific approach or technique that we miss other opportunities passing us by. It is a delicate balance that we are constantly assessing and checking in on as a team. By casting a wide net, this allows us to probe and assess a diverse variety of opportunities and then pick strategies and approaches that we deem best to move forward with.

Next, working in tandem with casting a wide net of opportunities, outreach. And we spend a LOT of time doing targeted outreach. This could be outreaching to potential companies we’d like to partner with, new researchers, specific rare disease consortia… and having many meetings per week with these stakeholders to figure out if and where they all fit into our therapeutic mission.

This leads nicely into my next point which is what we do a LOT of behind the scenes work to vet and assess potential opportunities before publicly announcing new initiatives and partnerships. This is not done with any intent to leave any part of our community out of the process. However, its important to highlight that not every opportunity that we explore is going to work, or is not best for our personal mission as an organization, which is okay! But we want to make sure that what we are communicating to our community are the relationships and partnerships that we have the utmost confidence in and fully support.

We also strategically build toolkits and resources to help push research forward by leaning on relationships that we have cultivated over time. For example, we have an excellent relationship with the Jackson Laboratory who has not only helped us create important tools for research discovery but also is committed to making them accessible to our current and future research partners. This saves us money, but most importantly, it saves us a LOT of time, which we are constantly working against.

Another big part of moving therapeutic development forward is holding a seat at the table of key stakeholder meetings. By this I mean having KIF1A.ORG representatives in the meetings where the nitty gritty details about therapeutic discovery are occurring. In a therapeutic development space, visibility is HUGE for rare disease organizations like KIF1A.ORG because, while we are happy to discuss scientific specifics, we also humanize and provide context for the science behind KIF1A which is instrumental in making sure everyone stays focused on our ultimate goal of finding treatments and cures for KAND.

And lastly, the most important way that we drive research forward is by being relentless. I don’t need to tell you all what it means to be relentless because our community is the embodiment of relentlessness every day of our lives. But just know that your relentless spirit infiltrated and motivates every decision and opportunity we have as an organization.

Now, what do we identify as our strengths that help move therapeutic development forward as an organization?

First, we move very quickly while working against a timeline that is historically moved very slowly. Therapeutic development does not move fast enough for the rare disease community: that’s a fact. We could accept that fact and move along at a pace that is too slow… but we aren’t going to so that. Instead, we challenge this timelines and utilize tools, connections and resources that allow us push the pace and reach our goals more quickly. This was especially made apparent in over the past year in the height of the COVID-19 pandemic. Sort of against all odds, in a time where the majority of the world was shut down to some extent, we still managed to make an extraordinary amount of progress by moving quickly, not taking no for an answer and challenging preexisting systems that are not serving out community in the way that they need to be.

We also create and provide a variety of different resources that influence our therapeutic development process. Some of these are resources that can be directly used in experiments such as patient derived stem cells that are now at the Coriell Institute. And a lot of these resources focus on science communication to make sure that all of our stakeholders, whoever they may be, have access to our current knowledge about KIF1A and KAND. For example, this can be in the form of Science Saturday, Research Simplified articles, or even target videos like our recent “What is KAND?” video.

A big strength and a major focus of the past year has been our ability to mobilize researchers, clinicians, and any other members that we need in our network to help move therapeutic development forward. It is amazing what can happen when you get brilliant minds all in the same place to discuss KIF1A, KAND and KAND therapies. So much progress can be made in even an hour’s time. However, getting those individuals together is a lot of work. This is why we’ve been holding our monthly Research Roundtable meetings: to provide this space for researchers to come together.

Last year we formalized all of our contacts by defining our KIF1A.ORG research network.

The KIF1A.ORG Research Network has many stakeholders, each who play an important role.

The most intuitive members of this network are researchers. Clinical researchers and clinicians, basic science or fundamental science researchers and translational researchers that help bridge our understanding from experiments that occur in a laboratory to what is actually happening on a clinical level in a human. This contingent of the research network is rapidly growing and what we are seeing is a really encouraging form of mentorship starting to occur. By this I mean we have long time KIF1A researchers and advocates like Dr. Wendy Chung and Chung lab team members and Dr. Cat Lutz from the Jackson Lab helping orient and bring other researchers up to speed on KIF1A and KAND. We are also seeing an influx of researchers into our network that have never worked on KAND before in their laboratories or clinics. This is fantastic news because this means we are drawing a larger workforce into our research network, finding more people to help tackle the complex questions that arise as a result of KAND.

Regarding the rest of our Research Network, we do like to think broadly about what contacts we have as an organization and what role and contribution can they bring to the Research Network? This extends to contracted research organizations which are organizations that we may contract out to do specific research projects. It also includes biotech and industry partnerships. We have had biotech representatives attend and also present at some of our research roundtable meetings. Investors and funders as well as thinking about the broader community like different rare disease organizations and of course our KIF1A.ORG community as well.

Part of identifying one’s strength or an organization’s strengths is realizing what type of work is best done in house and what type of work is best to outsource. For us we think about this in terms of specific therapies: what types of therapies can we directly drive as an organization with our contacts and resources and what should we be outsourcing?

For example, we have been very successful and continue to be successful in driving forward progress with small molecule compounds and specific types of drug therapies, and we will continue to drive these forward.

But we also recognize our limitations, for example, in exploring potential gene therapy or gene editing approaches to treatment. This is an area where we identify that it is most resourceful and efficient for us to partner up and outsource this work with larger companies that are more appropriately resourced to employ these technologies.

So, we’ve talked about who we are, how we operate and talked about our strengths. But when it come to a specific strategy regarding how we initiate, develop and support therapeutic options – how do we prioritize?

We take a “multiple shots on goal” approach. This means that we have many different therapeutic approaches being investigated at the same time. While these approaches may have different starting points, they will likely all converge into a similar pipeline that ultimately gets us to a clinical trial and therapy approval. We take these multiple shots on goal with the understanding that not every shot is going to work, and that’s okay. We need not fear failure. But, we DO need to make sure we are testing as many approaches as possible to ensure that we can find our success in a sea full of well-calculated attempts.

As far as our criteria for this “shots on goal” mindset we value:

Multiple ongoing efforts, especially in a range of different treatment options. In other words we don’t want to put all of our effort into small molecules or all of our effort into ASOs. We want to diversify our efforts so we can investigate as many options as possible.

We also need to have an internal workflow that allows us to evaluate and reevaluate how therapeutic approaches are working. If a compound or a therapy doesn’t not appear that it is going to be the hit that we need, we want to figure that out as early as possible so we can push resources to another candidate.

And lastly, our attempts need to be conducted in parallel, not one at a time. Why? Because as you know, time is not on our side. We have no time for linear attempts; therefore we have created a system that allows us to balance multiple attempts at once.

And in the context of our shots on goal approach, I want to take a moment to discuss two words that have a tendency to be viewed as scary or negative when we are talking about progresses, and those two words are risk and failure.

We as an organization and we as a community need to recognize that in order to make progress, we must take risks. This is because we don’t have all of the information we need to take risk-less chances. But instead of being stagnant and waiting until we do have all of that information, we need to move forward by taking well-calculated risks baked up by the data and knowledge that we DO have.

Now, with risk comes the chance of failure. And to us, failure is an extremely important and welcomed part of the process. If we aren’t failing, we aren’t trying hard enough. This is why we like to reframe this mindset by saying, “it’s not that we failed, it’s that we tried and because we tried, we learned something new”. We have already tried compounds on our KIF1A models that have failed. In this context, this would mean that a specific compound did not yield a result that was anticipated. And again, that’s okay. Because failure is actually very informative in terms of therapeutic development. We can learn equally as much if not more from failure than we do from success.

Risk and failure are two important components of the science discovery behind therapeutic development. But how exactly does scientific discovery work?

Scientific discovery is commonly marketed like this. You have an idea “A”, then do some very streamlined work and eventually arrive at “B”, you conclusion or your new knowledge. This is how news stories and articles tend to describe the scientific process. And I am here to tell you today that this is wrong. Because while we expect scientific discovery to look like this, in reality…

It looks a lot more like this! Instead of this simple and straight forward process, scientists are often working through a process like this. Where there is a lot of testing and retesting, confusing findings and dead-end pathways… but ultimately still moving forward to find answers. Scientists gain SO much more information and understanding through THIS process than they do THIS process.

This process that I’ve depicted here can also be referred to as the scientific method.

The scientific method is a process employed for experimentation and acquiring knowledge about a specific topic that has clear steps to test and assess scientific questions. In other words, the scientific method is a way for people to study and learn things. While this may look like a complex process, it does end up being pretty intuitive, and I would bet that many of you are using the scientific method in your day to day lives to help you make choices and informed decisions.

The process starts with an observation. Something caught your eye and made you take notice. In the context of KIF1A this could be the observation of a KIF1A mutation or variant. From this observation, we next generate a question. “How is this mutation affecting KIF1A function?”

Once we have our question, we do a lot of research to formulate what is called a hypothesis. This is a way to describe an educated guess about the question you’ve come up with. Emphasis on the word guess here because it truly is a guess- if we already had the answer, we wouldn’t need to go through this process! But this is an example of how risk is involved in the scientific method. Your hypothesis is a statement that you believe will be the answer to your experimental question. Of note, hypothesis are generally either true or false. Proven or not proven. This level of simplicity is what makes this aspect of the scientific method so powerful and repeatable.

With a question and hypothesis established, we next need to test our hypothesis experimentally to figure out if it is true or false. From the experiments that are conducted, you will receive data that either supports your hypothesis or refutes your hypothesis. In both cases, there is a certain element of revising or retesting this hypothesis before ultimately communicating the results of your findings.

This scientific method process is at the heart of all research discoveries and therapeutic development projects that we will discuss in our later videos.

To review, in this video we have discussed:

  • Who we are as an organization
  • How we drive therapeutic development forward
  • Our strengths as an organization
  • Our therapeutic shots on goal strategy
  • The importance of risk and failure in therapeutic development
  • And reviewed the process of scientific discovery and the scientific method

Thanks for watching and if you have any questions feel free to email myself, Dr. Dominique Lessard, Chief Science officer of KIF1A.ORG.