Regulations against curing genetic diseases in animals.

This is David Ishee.

David loves dogs and wants to correct what humans have done to them.  As dog breeder and citizen scientist he realized that dogs have more genetic diseases (over 600) than any other species on the planet because we have been genetically modifying them for certain traits like shorter snouts, smaller heads… and spots. They’re suffering because looks, “breed purity” and winning shows has been more important than health, function, and quality of life for hundreds of years now.

After several centuries of inbreeding, humans have genetically altered Dalmatians to have their well known white coat with black spots and also to have several genetic health defects.

David was most interested how nearly all Dalmatians develop hyperuricemia thanks to a single mutated gene — the SLC2A9 gene. Almost all Dalmatians lack a working copy of the SLC2A9 gene which is needed to get uric acid out of the body. As a result the uric acid can build up into stones that block the urethra and might lead to a burst bladder.

One attempt to correct these genetic problem was made by the Dalmatian-Pointer Backcross Project. After ten generations a single line of dalmatians is now 99.99% genetically similar to other purebred Dalmatians and has a working copy of the SLC249 gene.

The problems are that they still carry the mutated copy recessively. They still have 3 genes that can be traced back to pointer origins, which causes most dalmatian pure breeders to reject them as mutts and even though they can now be registered with the AKC as dalmatians they have a special mark on their pedigree which amounts to the scarlet letter forever marking them as “impure”. To try and breed out the recessive gene within an already small part of the population would mean further inbreeding and likely create new health problems and it would require isolation from the rest of the dalmatian population forever isolating them from the unmutated gene.

That’s where David and the CRISPR gene editing technology comes in. CRISPR is a new gene editing technology that allows precise genetic edits on a scale and at a price we’ve never had before. The CRISPR system basically uses special RNA guided proteins to very accurately cut DNA near a mutation allowing the cells natural repair mechanisms to fix the cut and sometimes to fix the mutation during the repair process especially when combined with a short section of template DNA showing the cell what the correct DNA sequence should be. CRISPR is molecular surgery that allows us to stimulate and guide the natural DNA repair mechanisms of the cell to correct these harmful mutations. In this case there is a T in the genetic code of their SLC2A9 gene where there should be a G. This is a gene found in almost every animal species on the planet including humans. It makes a transport protein that moves uric acid out of the blood stream and into the urine. Mutations in SLC2A9 are connected with Hyperuricemia, Gout, Parkinson’s and Alzheimer’s because this gene is very important in keeping toxic bodily waste products from building up in the blood stream. This can be corrected by repairing this one gene out of 19,300 Dalmatian genes.

The method is to use CRISPR in combination with another technique called “Sperm Mediated Gene Transfer” he should be able to repair the DNA in collected sperm cells and use those for artificial insemination, fixing the mutation without bringing in any other breeds. This could be done by dozens of breeders with hundreds of dogs making a diverse healthy generation to breed from. By making this small repair he will be able to fix what hundreds of years on inbreeding created without the problems and stigma of backcross breeding. This same technique can also be applied to other breeds and other diseases as a method to eliminate harmful mutations without sacrificing genetic diversity.

Dog breeders, citizen scientists and the biology community are interested in seeing the results of this projects. He’s been contacted by many dalmatian breeders eager to see a real cure for this disease. He has researched and planned for it for years now and had this plan evaluated by several molecular biologists from universities and biotechnology companies from all over the world.

The problem is that the FDA wants to classify dogs as new animal drugs. Yes, dogs would be considered drugs.

The FDA updated their existing guidance for genetically engineered animals to include genome editing two weeks after David contacted them to let them know that the animals wouldn’t be transgenic and so they weren’t FDA regulated. The timing and exact nature of the new proposed regulations following that meeting are highly suspicious. They blogged that “When animals are produced using genome editing, FDA has determined that, unless otherwise excluded, the portion of an animal’s genome that has been intentionally altered, whether mediated by rDNA or modern genome editing technologies, is a drug because it is intended to alter the structure or function of the animal and, thus, subject to regulation under our provisions for new animal drugs.”

The problem of course is that “the portion of the animal’s genome” is woven into every bit of the animal. So dogs = drugs.

They went further though and have said that, despite the same gene edit being done, each puppy born would be considered a new drug. Legally the FDA only has authority to regulate the sale of food, drugs, and cosmetics. I suppose they didn’t think they could convince anyone that dogs were food or cosmetics so they’re trying drugs.

Each new animal drug requires a separate Investigational New Animal Drug (INAD) application and $100,000 fee, annually. Convenient and very profitable for the FDA.

There are two issues here: first, this kind of genetic repair is being lumped in to the same bucket with transferring genes from separate species and treated as the same risk — but nothing new is being created, just repairing a mutation and returning the DNA to its natural healthy sequence. Second, this new regulation is only pretending to be intended to mitigate any risks at all. On very bottom of the third page of this new proposed regulation, in the fine print there is an exemption made for “random mutagenesis”.

Which means, under this new regulation genetically mutated animals created by exposing egg cells or sperm to gamma rays or mutagenic chemicals to randomly alter their DNA would pose no risks at all, not be drugs and be exempt from these new requirements. Clearly this regulation isn’t being made to mitigate risks, protect the animals, people, or the environment, but to control who has access to these “modern molecular technologies”. Ensuring they can only be used by the wealthiest corporations and government agencies, who can use these new technologies to make new cures and treatments and sell them at the very highest price. The idea that a bunch of dog breeders could use this technology to cure genetic diseases without their say so seems to be something they are actively apposed to, despite the complete proactive cooperation this breeder has shown the FDA over the years by initiating contact and by providing them with all the information on the project they have asked for.

There is hope though. The new regulations aren’t formal yet and there is an open public comment period. This is the opportunity for all of us to speak up and to tell the FDA that we want rational risk based regulation of our Food, Drugs and Cosmetics from them and not irresponsible overreach that dooms thousands of animals every year to avoidable death and suffering.

The FDA says ” We are also seeking input on whether certain types of genome editing in animals pose low or no significant risk, and we may modify our regulatory approach based on this input.”

Please leave a comment with the FDA and voice your opinion and do so before April 19 2017, that’s when they’ll start reading the public comments. If you care about the health of animals, the future freedom of technology or about holding government agencies to only making rational risk based regulations, please click comment and leave your thoughts.

Click here to make your comments.

Below is some input you can give them, feel free to copy and paste, or just tell them dogs aren’t drugs in your own words:

These new technologies allow animal breeders the opportunities to repair harmful genetic disease causing mutations by restoring animals to their wild type genetic sequences.

These new regulations put significant barriers in the way of those efforts, the fundamental perspective of the animal itself as a “new animal drug” in those cases doesn’t match the legal definition of a “new animal drug”. I’m also very wary of the implications of classifying any genome as a drug legally.

FD&C 201(v)

(v) The term “new animal drug” means any drug intended for use for animals other than man, including any drug intended for use in animal feed but not including such animal feed,—
(1) the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof; except that such a drug not so recognized shall not be deemed to be a “new animal drug” if at any time prior to June 25, 1938, it was subject to the Food and Drug Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; or
(2) the composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions.
Provided that any drug intended for minor use or use in a minor species that is not the subject of a final regulation published by the Secretary through notice and comment rulemaking finding that the criteria of paragraphs (1) and (2) have not been met (or that the exception to the criterion in paragraph (1) has been met) is a new animal drug.

Section (1) states that drugs which are “generally recognized as safe” are not “new animal drugs”. Clearly wildtype genes are generally recognized as safe and have been used to material extent and for material time regardless of the origins of the sequence. There is no fundamental difference between identical genetic sequences produced by evolution, selective breeding, random mutagenesis, or modern molecular technologies, therefore no fundamental difference in their risk profiles.

If the FDA is regulating in a risk-based, scientific manner then clearly regulating based on the method used to produce a sequence isn’t the correct approach. Why would causing a genetic disease by radiation induced mutagenisis be assumed safe but reversing a disease causing mutation via modern molecular technologies be assumed unsafe? This revision is clearly not based on mitigating risks to people, animals or the environment.

Beyond that this approach creates the possibility for situations that can’t be clearly regulated. For example, if a breeder repaired a genetic disease and restored an animal to it’s natural genetic sequence that animal and it’s offspring would be considered a drug. If the durg/animal were then bred to an animal of wild type with an identical gene sequence in the affected area, would the pups be legally drugs or not? The identical nature of the gene sequences of both parents makes it impossible to tell if they inherited it from the drug/parent or the non-drug parent.

if a genome edit is made using CRISPR, say a nucleotide is added then it’s removed from the next generation by natural mutation or random mutagenisis is the regulated article gone and that second generation is not a drug?

If a genome edit is made to a male mammal on the Y chromosome will his daughters be drugs since they couldn’t have inherited the change?

In the event of a deletion what exactly is the article, the missing nucleotides?

I have two general suggestions for different approaches that avoid some of these issues.

1. Regulate based on the risk not the breeding method, there is no scientific reason to bias regulations against modern breeding techniques in favor of older less exact methods.

2. If you must bias regulations against advance breeding methods make an exception for “restorative edits” or “genomic repair” where no novel sequences are introduced into a given species. Those genomic alterations that only transpose wild type sequences between animals within a single species. Since nothing novel is created other than gene flow within a species, it’s risk profile is indistinguishable from selective breeding, so reasonably the genomes of those animals should have the same legal status. Considering there is an existing exemption for random mutagenisis despite its risks, this shouldn’t be an issue, and it will allow breeders the freedom to use advanced techniques to repair the thousands of genetic diseases that have accumulated in our domestic animals because of the limits of selective breeding.

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