Advancing Gene Therapy with Chameleon Biosciences
At Tachyon, we seek to discover companies developing platform technologies that address limitations affecting entire fields and thereby prevent therapeutics from reaching patient groups that could otherwise stand to benefit.
When we investigated Chameleon Biosciences, its technology presented an exciting opportunity to unlock the full potential of AAV gene therapies for several classes of patients, and the company’s team showed unparalleled experience in the space to execute on their vision. We’re excited to share our thoughts on how we believe Chameleon’s platform can overcome several obstacles faced by other companies in the field of AAV gene therapy, and why we decided to invest in their recent Seed Round.
Gene Therapy’s Disruptive Potential and Key Limitations
Genetic disorders are a broad category of debilitating and often life-threatening diseases that are caused by mutations in a person’s DNA. The vast majority of identified genetic diseases, of which there are thousands, have no therapeutic options or are treated by way of drugs addressing symptoms rather than the underlying genetic cause.
Gene therapy is a rapidly evolving treatment modality that addresses disease at the genetic level by delivering replacement genes to patients. The genetic material can either be delivered directly into the patient’s body (in vivo therapy) or it can be delivered to cells that have been removed from a patient and are then reintroduced into the body (ex vivo gene therapy). What is most disruptive about gene therapies, and the reason why they have been received with such enthusiasm, is their potential to provide a long-lasting or even permanent cure to patients.
Gene therapies have already been approved to treat various inherited conditions, such as sickle cell anemia (a red blood cell disease), Leber congenital amaurosis (an eye disease), spinal muscular atrophy (a motor neuron disease), and various forms of cancer (mostly blood-related cancers). In vivo gene therapies need to be delivered to particular cells in the specific area of the body that needs treatment, and in order to do so, researchers use so-called “vectors”. Vectors are vehicles designed to deliver therapeutic genetic material, such as a working gene, directly into a cell. A particular type of vector, AAV (adeno-associated virus) vectors, have emerged as one of the most promising systems for gene delivery, and their use has been validated in clinical trials for the treatment of a wide range of genetic diseases.
As much as they provide promise, AAV therapies also pose considerable challenges. The most important one is that AAV therapies currently can only be administered once - in a single dose, because that first exposure to AAV vectors triggers the creation of antibodies in the host, whose purpose is to destroy AAV vectors upon future contact. This means that second and further doses of AAV therapies are destroyed by the patient’s antibodies before they can reach the right cells for treatment. This creates key limitations for AAV-delivered gene therapies because it makes them:
- Incompatible with ~50% of adults. Around half of adults harbor preexisting AAV antibodies, making them refractory to AAV gene therapy. Patients who have had previous exposure to AAVs, such as through natural infection or previous therapy, develop antibodies that would destroy the AAV upon delivery.
- Not apt for children. Children’s organs and tissues are not fully developed. Therefore, in order to treat children successfully through gene therapy, they would require multiple doses of therapy to accommodate the changing number of cells. For this reason, they are often excluded from clinical trials.
- Potentially toxic. Given AAV gene therapies can only be administered once, higher doses are sometimes required to achieve the desired therapeutic effect in a single attempt, increasing the dangers of toxicity and lethal immune response.
Chameleon has developed a solution that enables multiple doses of AAV-delivered gene therapies by allowing the delivering AAV vectors to evade the immune system, thereby opening the door to multi-dosage gene therapy and limiting the risks associated with strong immune responses.
Their technology works by wrapping the AAV vector in a lipid barrier coated with immune-suppressing protein factors. Interestingly, the proteins that Chameleon uses, PDL-1 and CTLA-4, are targets of various cancer therapies because tumors often evolve to express them in order to evade the immune system. Together, the protein factors and lipid membrane shield the AAV from recognition by neutralizing antibodies and suppress immune system reactions.
By circumventing the immune response, Chameleon’s EVADER technology addresses the three challenges we previously presented. Using this engineered AAV, the large population of adults with pre-existing antibodies can be dosed effectively, as the AAV vector will be equipped to evade existing antibodies. Second, because most gene therapies lose effectiveness over time—as the cells with modified DNA become diluted or die— the ability to re-dose is a necessity for the prolonged success of gene therapies. By enabling multi-dosing, Chameleon’s technology makes AAV gene therapy accessible to children and widens the therapeutic potential for adults needing supplemental doses. Additionally, without the added pressure of a one-dose limit, safety can be favored and lower doses can be administered with greater efficiency over time.
Chameleon’s starting pipeline focuses on three indications: severe hemophilia B, Niemann-Pick Type C (“childhood Alzheimers”), and Mitochondrial NeurogastroIntestinal Encephalomyopathy (MNGIE). The last two of these currently don’t have FDA-approved treatments, but if a lasting cure through gene therapy can be successfully introduced, patients who often do not survive past the age of 20 could see their lives transformed.
However, Chameleon’s EVADER technology is broadly compatible with a wide range of AAV gene therapies, meaning it can be mobilized to target many types of genetic disorders. The wide applicability of the EVADER platform opens the doors to many possible collaborations with other biotech companies to ramp up the development of FDA-approved gene therapies across a multitude of indications.
Why Tachyon is excited about Chameleon
At Tachyon we invest early in disruptive platforms built on top of world-class research with strong IP. But strong sound science is not enough. A clear market and a team able to execute are key parts of the equation. The following 4 points are not exhaustive but hopefully provide you with a window into the rationale behind our investment in Chameleon. We’re excited to have joined their journey!
- Sound science with wide applicability
The two proteins used by Chameleon in the EVADER technology have extensive clinical validation in performing their intended function as modulators of immune response. In addition, EVADER’s wide compatibility with other AAV gene therapies and across diverse indications holds enormous therapeutic potential. This winning combination positions Chameleon to function both as a platform company offering its technology to others developing gene therapies and as a single-asset company spinning out its own gene therapies.
- Strong team with deep expertise in gene therapy
Genine Winslow, Chameleon’s co-founder, spent years working at the forefront of gene therapy development. With a deep understanding of the limitations and obstacles of gene therapies, she founded Chameleon to develop the next generation of AAV gene therapies. Chameleon is built on technology that originated from the lab led by Professor Casey Maguire - one of Chameleon’s co-founder - at Harvard Medical School. In addition, Chameleon’s core team and advisors have decades of deep expertise in the science, clinical development, and manufacturing of AAV gene therapies, in addition to a strong network of potential commercial partners and licensors at their previous companies. Together, they are poised to ensure that the EVADER technology is successfully delivered to market.
- EVADER addresses a clear unmet medical need
Nearly half of all patients are excluded from treatment with existing gene therapies due to existing antibodies, and those who are eligible stand to benefit from a lower strength, multi-dosing strategy to overcome the obstacle of dose-limiting toxicities. The EVADER platform can have a game-changing impact on the development of dozens of gene therapies and greatly expand the number of patients that can be treated with them.
- Big pharma has shown strong positive market signals for gene therapies
In less than five years, big pharma (Roche, Novartis, Astellas, and others) have paid over 20 billion USD upfront to acquire various gene therapy companies. This strong market signal is encouraging for the growth and timing of Chameleon’s technology and gene therapies as a whole.