The gene KIF1A encodes a protein that powers the transport of materials within nerve cells. Mutations in the gene cause changes in the structure of the KIF1A protein that impact its function and result in what are called KIF1A-associated neurological disorders (KAND). These disorders cause a range of developmental and degenerative problems that include intellectual disabilities, autism, epilepsy, microcephaly, encephalopathies, and other severe conditions.
Together with his collaborators Wendy Chung, MD, PhD, Chair of the Department Pediatrics at Boston Children’s Hospital at Harvard Medical School, and Cryo-EM specialist Hernando Sosa, PhD, Professor of Biochemistry at Einstein, Gennerich is inching ever closer to developing a treatment.
This conversation has been edited for length and clarity.
Cure: Tell us about your background.
Arne Gennerich: I originally trained as an electrical engineer and physicist. During my PhD in Germany, I developed a microscope to observe tiny processes inside cells, which led to my fascination with how mitochondria, the cell's power plants, are transported over long distances in neurons. This movement is powered by tiny molecular machines called kinesin motors.
Intrigued by this, I pursued postdoctoral research at UC San Francisco in Ron Vale’s lab, where kinesins were discovered. I learned how to study these motors using purified proteins and watched them “walk” along microtubules, the cell’s internal railways. Combining my engineering skills with biology, I decided to focus on these motors in my own lab.
Cure: Interesting — can you bring these motors into context? How do they function in the body?
Gennerich: Kinesin motors are made up of two identical proteins that form a "dimer." One end has a "tail" that holds the two proteins together and attaches to cargo, while the other end has two "feet" that walk along microtubules.
These motors are remarkable because they can take hundreds of steps without letting go. As they move cargo through the thick cytoplasm of the cell, they generate force and perform work to transport materials. To power this movement, kinesin motors use ATP, the cell’s energy currency, which is produced by mitochondria.
My lab studies different motor proteins, but one called KIF1A fascinates me the most because it can take thousands of steps without falling off the track. Given its critical role in neurons, mutations in KIF1A can cause serious diseases.
Cure: How do KIF1A mutations cause these disorders?
Gennerich: The protein that KIF1A encodes plays a crucial role in healthy cells by transporting materials from the cell body to the axon terminals of neurons, which is essential for neurons to communicate. It also helps move the nuclei in developing neurons, which is especially important for brain development.
However, when KIF1A is mutated, the expressed protein is abnormal, which disrupts either its ability to move along microtubules or attach to cargo. If the protein can’t bind properly, brain development can be affected. Alternatively, if its speed, travel distance, or ability to generate force is attenuated, neurodevelopmental issues may occur. These developmental and degenerative problems together lead to KAND.
KAND diseases can be devastating — children may lose the ability to walk, see, or speak, and some who initially develop normally may regress due to neurodegenerative effects. Sadly, many do not survive.
Cure: What is the number of people who have KAND?
Gennerich: The number seems to be growing rapidly. In 2017, Luke Rosen and his wife Sally, parents of a child with a KIF1A mutation, founded KIF1A.org. At that time, only a few patients were registered. But as more families with developmentally delayed children started getting whole genome sequencing, more cases of KIF1A mutations were identified.
By 2022, 500 patients were registered with KIF1A.org, and now the number is close to 700 children. One of my collaborators, Wendy Chung, MD, PhD, a Professor of Pediatrics at Harvard Medical School and the leading clinician for KAND patients worldwide, believes that mutations in KIF1A could also be linked to diseases like Rett syndrome and Charcot-Marie-Tooth disease. We, therefore, suspect there could be tens of thousands of children worldwide with KIF1A mutations, meaning the current numbers are likely a big underestimate.
Cure: Is there any treatment?
Gennerich: Yes. Most patients have what’s called heterozygous KIF1A variants, meaning only one of the two genes that encode KIF1A protein is mutated. There is a treatment called antisense oligonucleotides (ASOs) that bind to the mutant gene and prevent its expression, allowing only the normal, or wild-type, gene to be expressed. The ASO treatment must be injected into the spinal canal every two months. Luke and Sally Rosen’s daughter, Susannah, received ASO treatment, and after just two doses, she showed significant improvement. Before the treatment, she couldn't stand up alone or communicate properly and suffered from severe tremors and seizures. After treatment, she was able to stand on her own, speak sentences, and her seizures reduces from hundreds a day to just a few per week, with her tremors resolved. This shows that some of the degenerative effects of KIF1A are reversible if treated early enough.
Cure: If the ASO treatment is available, why develop a new treatment?
Gennerich: The ASO discovery and development were provided cost-free by n-Lorem, a nonprofit organization based in California that offers lifetime support for patients. While n-Lorem covers the cost of the ASO treatment, which is estimated at $1 million per patient, the overall expenses, including clinical care and hospital stays, can total around $2 million.
Because ASO therapy is still extremely costly, we need alternative approaches. The small-molecule therapy we’re developing should be much more cost-effective, allowing patients to receive treatment as often as necessary to maintain the benefits.
Cure: How did the XSeed Award help further your research?
Gennerich: When we began studying the KIF1A gene and protein, there were no high-resolution structures of the protein — previous ones lacked important details. With funding from the XSeed Award, which I shared with my collaborator Hernando Sosa, an internationally renowned cryo-EM expert, we solved the first high-resolution structures of both the normal KIF1A protein and a disease-causing mutant protein, KIF1A-P305L. These structures showed us how the mutation alters KIF1A’s interactions with microtubules, helping us understand how KAND develops.
Cure. How will you build upon this initial work?
Gennerich: We will use the remaining XSeed funds to run computer-based drug screens using these structures. By comparing the normal (wild-type) KIF1A protein structure to the mutant structure, a computer program can identify differences. The program is connected to a database of tens of millions of small molecules. If we find a molecule that binds specifically to the mutant and not the wild-type, we will test its effects in our assays.
Our goal is to find a small molecule that improves the function of the mutant protein, helping it behave more like the wild-type. Ultimately, we’re aiming to restore near-normal function in the mutant.
Cure: Could you scale this research?
Gennerich: We believe so. Our long-term goal is to create a start-up company focused on structure-based drug design. This would involve solving the structures of protein complexes and developing drugs that either reduce the function of a target protein (in cases where it’s essential for cancer-cell division) or restore function of a mutant protein.
Cure: Where does your work currently stand?
Gennerich: We’re now ready to begin computational drug screening for the first mutant. Once we identify small molecules that bind specifically to the mutant, we’ll test them in my lab to see if they can restore its function. If a molecule shows positive effects, we will solve the structure of the mutant bound to the small molecule and work with a chemist to improve its binding affinity.
Once we have a promising candidate, we will test it in a KAND mutant mouse model, which is available from The Jackson Laboratory for Genomic Medicine in Connecticut. If the molecule is safe and has no toxic side effects, our clinical collaborators will seek FDA approval to evaluate it in a patient who needs it. Because these diseases are rare and often life-threatening, the FDA has programs to accelerate development of drugs when no other treatments are available, ensuring that patients with rare diseases receive care as quickly as possible.
Now in its fourth year, the XSeed Award program provides up to $250,000 grants to New York City minority- and women-led life science and healthcare startups working on novel preclinical drug development projects. Winning teams also join the ecosystem of Cure.®, a healthcare innovation campus in New York City. The teams receive peer-learning and office hours with investors, entrepreneurs, and business experts. Learn more.