Deep Knowledge Ventures to Support BioViva's Human Gene Therapy Development

Fortes fortuna iuvat, as they say. I'm pleased to see that the BioViva principals have attracted the support of Deep Knowledge Life Sciences as they continue to bootstrap their very intentionally disruptive gene therapy startup:

Deep Knowledge Life Sciences and BioViva announce partnership

"BioViva aims to make gene therapy affordable to everyone. Dmitry Kaminskiy, the founding partner of Deep Knowledge Life Sciences, is enthusiastically funding gene therapy, and is himself an early adopter." said BioViva CEO Elizabeth Parrish, adding "We both want to see a world where investors actually live their legacy instead of just leaving it", alluding to a possible future trend. Parrish made headlines in 2015 when she travelled to an undisclosed location outside the US and personally underwent two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion. It was a gesture intended to prove the safety of the therapies and clear the road ahead for human trials in the US. Months later, BioViva are tracking her results and she has reported no negative side-effects. "I believed the biotech industry had become over-regulated and that the prevailing model was unlikely to bring new therapies to market in our lifetime. What we needed was a company that would treat diseased patients with no other options and then develop these treatments into preventative medicines. And thus was born BioViva in 2015."

For Dmitry Kaminskiy it's not all about the portfolio. He wants to shift the entire industry up a gear, and put an end to the lack of vision he believes has mired biotechnology for decades: "Millions of human lives are affected by diseases with a genetic component. The sooner we can bring affordable gene therapies and other cell therapies to market, the more needless deaths can be avoided."

I regard the shared vision of bypassing excessive regulation in medical development to be somewhat more important than the exact nature of the therapies under development today. Rapid, effective passage to the clinic will be the legacy here, the opening of a door that will see an increasing number of developers in every important field of medicine adopting a fast path to medical tourism and clinical availability outside the US and Europe, transparency of ongoing results, and a sensible degree of safely data. The stem cell field and countless patients benefited greatly from this sort of approach over the past fifteen years, and it really should be the standard, not the exception.

What constitutes a sensible degree of safety data? That should up to companies and patients to decide upon for themselves, but it is certainly far, far less than the FDA presently insists upon. The FDA leadership are not primarily concerned with safety at all, but rather the potential political fallout that might result from approving any any therapy, ever. There is no such thing as a safe medical treatment, but the media can pounce at random on any death, and the defense put up in advance by FDA career bureaucrats is to demand as much expense and data as possible from applicants. Few people seem to care about the potential therapies that never make it through the process, or are never submitted because there is no possible profit - those losses are invisible, but they are measured in lives, not money. These perverse incentives, rife in every government agency, is why the cost of developing drugs is huge, why the process is lengthy and drawn out beyond all common sense, and why the cost has doubled in the past decade. These imposes costs are pointless and unnecessary, and a huge burden on progress. It is long past time to evade the FDA and take the road of medical tourism, transparency from companies, educated customers, and sane levels of testing and development cost.

BioViva has demonstrated prototype follistatin and telomerase gene therapies in the first human volunteer. If successful, and with a enough uptake in cells, the former should provide increased muscle mass and thus compensate partially for the sarcopenia that accompanies aging, while the latter may globally increase stem cell activity, offsetting to some limited degree the decline that occurs with age. To my eyes follistatin and similar myostatin gene therapies are about as low risk as any genetic edit can be before it has been used by thousands of people. Myostatin blockers of various sorts have been trialed in humans with positive results, and scores of animal studies for follistatin and myostatin gene therapies have taken place since the turn of the century. There are natural human and animal myostatin loss of function mutants to study as well, and most seem to do pretty well with their extra muscle tissue. Telomerase gene therapy on the other hand strikes me as being more risky. It clearly extends life and improves health in mice, but mice have very different telomere and telomerase dynamics when compared to humans. There is the strong possibility that telomerase therapies will boost cancer incidence in humans, even though they don't do that in mice. At some point it has to be tried based on the intriguing animal study results, but I wouldn't want to be first in line.

There is no reason for gene therapies to be expensive once they are out of their initial phase of development and early adoption. This is the age of CRISPR, an basis for gene therapy that makes genetic editing so cheap and easy that near every life science laboratory can now undertake this research. A gene therapy treatment to enhance capabilities or compensate somewhat for one or more of the losses of aging, such as myostatin knockout or follistatin overexpression, will trend towards becoming a mass produced infusion, the same for everyone, administered by a bored clinician, and with limited need for followup attention from a physician. All of the complexity is baked into the manufacturing process, and the cost will scale down as the production runs grow large. Unlike drugs for medical conditions, the target market here is every adult human being: the economies of scale and competition will be more like like those for present day childhood vaccinations than other types of medication, and the price will accordingly fall to the same low level.

So, I hope to see BioViva prosper in their effort to shake up clinical translation, and demonstrate that no-one really needs the FDA in order to responsibly place the next generation of therapies in the hands of patients. They have picked a set of treatments likely to attract a lot of interested parties to the clinics that will provide them, and the advent of CRISPR-based gene therapies will make expansion to other very interesting therapies quite plausible. Things should become interesting in the years ahead, I believe.

Comments

"Rapid, effective passage to the clinic will be the legacy here, the opening of a door that will see an increasing number of developers in every important field of medicine adopting a fast path to medical tourism and clinical availability outside the US and Europe, transparency of ongoing results, and a sensible degree of safely data. The stem cell field and countless patients benefited greatly from this sort of approach over the past fifteen years, and it really should be the standard, not the exception."

That doesn't seem to be the case: https://www.youtube.com/watch?v=c0XK2hV_UO0#t=39m58s (until 52:00 aprox.)

Posted by: Antonio at April 19th, 2016 7:33 PM

"There is no reason for gene therapies to be expensive once they are out of their initial phase of development and early adoption. This is the age of CRISPR, an basis for gene therapy that makes genetic editing so cheap and easy that near every life science laboratory can now undertake this research. A gene therapy treatment to enhance capabilities or compensate somewhat for one or more of the losses of aging, such as myostatin knockout or follistatin overexpression, will trend towards becoming a mass produced infusion, the same for everyone, administered by a bored clinician, and with limited need for followup attention from a physician. All of the complexity is baked into the manufacturing process, and the cost will scale down as the production runs grow large. Unlike drugs for medical conditions, the target market here is every adult human being: the economies of scale and competition will be more like like those for present day childhood vaccinations than other types of medication, and the price will accordingly fall to the same low level."

Um, didn't Michael Rae say that CRISPR/Cas9 is not useful for in vivo gene therapy yet on April 8th?

"As to the CRISPR/Cas9 system specifically: this is certainly a very useful tool for biomedical research, with utility for delivery of some SENS therapies as well - notably, editing stem cells to enable some therapeutics (and to make them impregnable to cancer), because those can be modified ex vivo, and defective cells can be screened and discarded, while successful transfectants can be expanded and seeded back into the tissue.

This kind of approach can also be used for nearer-term medical applications not directly related to rejuvenation goals as such: for instance, the Regeneron/Intellia agreement highlighted by Jim, involving ex vivo manipulation of haematopoietic cells for CAR-T cell therapy and other haematopoietic applications, as well as for liver cells in people receiving a liver transplant as part of treatment for hereditary transthyretin amyloidosis resulting from an aggregation-prone mutant transthyretin gene (a quite different problem from dealing with senile systemic amyloidosis, where the normal, wild-type protein aggregates due to stochastic damage).

But your (Barbara's) implicit premise seems to be that the CRISPR/Cas9 system could easily be used for somatic gene therapy - ie, introducing therapeutic genes into existing tissue in situ. And if you didn't mean that, such is certainly the explicit premise of others in the comments to this thread, and in previous comments in FA! to which I've not previously responded. In fact, using the CRISPR/Cas9 system for this purpose would require a great deal of innovation, including the emergence of strategies that no one has yet identified, even in principle.

For one thing, CRISPR/Cas9 does not come with any kind of vector system to deliver both components of it, and we don't have a sufficiently safe and effective delivery vector for it, although people are certainly working on delivery systems all the time. And whereas most delivery systems for gene therapy currently in use are for a single active component, it's actually at the moment very difficult even in cell culture to assure the coincident presence (and expression, as relevant), in the same cell at once, of all of the components of the system (the Cas9 exonuclease, the guide RNA, and the exogenous repair template) - let alone to do this in vivo across an entire somatic tissue. Additionally, the payload size that the system can handle is as of yet far too limited to be used for any kind of gene therapy useful to us, although people are working on that, too.

There are much larger problems, however, that are more central to the genome-editing mechanism of the system itself. The system works because the Cas9 endonuclease makes double-strand breaks in the host cell genome (or, using the trickier, engineered "dual nickase" system, you use two modified Cas9s that each make its own single-strand breaks at one end of the desired insertion site) at a site determined by the guide RNA, and the cell's DNA repair machinery "repairs" the break with new genetic material introduced in a separate repair template. The cell can use one of two DNA repair mechanisms to do this: the Non-Homologous End Joining (NHEJ) pathway or the Homology Directed Repair (HDR) pathway.

NHEJ is more or less OK for making decent-sized loss-of-function mutations (which scientists often want to do), but is too sloppy to be used for insertion of therapeutic genes, whether in mice or in humans: it often leaves small insertions or deletions that bridge over the site of the break in the strand, resulting in either frameshift mutations or premature stop codons within the open reading frame of the gene, resulting in either a protein that is prematurely truncated and useless or producing useless mRNA that just gets degraded by nonsense-mediated decay (or, theoretically, even a gene with a deleterious gain-of-function mutation, though I've never heard this raised as a serious prospect).

HDR is very precise, but it has a very low (<10% of modified alleles) efficiency, and it is only active in cells that are actively in the process of dividing, making it useless for introducing therapeutic genes into mature neurons or heart and skeletal muscle cells, and for substantial numbers of cells in organs like the liver and the skin at any given time."

Posted by: Jim at April 19th, 2016 8:51 PM

@Antonio: Opinions of course differ on that topic.

Posted by: Reason at April 19th, 2016 9:13 PM

"Opinions of course differ on that topic."

Well, Antonio is not a big fan of freedom and the free market so his opinion will always differ on anything that is not regulated and not under government control, irrespective of the benefits for mankind.

I see three problems with medical tourism that will vanish soon.

1) Working treatments like gene therapy are still very expensive and require skilled personal. So if you are a healthy doctor or scientist, you probably earn very good money and have no incentive to move abroad and risk everything (family, wealth etc.) for a vague undertaking. Even if you are ill, you will probably secretly use your lab at work but you won't move abroad. Liz didn't start BioViva for fun but because her son is ill and some genetic diseases run in her family. She didn't do it for the money, she did it because it was the right thing to do. She is a wonderful person and I wish her all the best.

2) Mass production of respective therapies hasn't started, yet. We still need a good vehicle for gene therapy but we are getting there. As soon as it becomes easier to apply gene therapy we will see more supply abroad.

3) BioViva is an innovator, there are no other companies that do the same. Hence, potential competitors are reluctant to enter the market. As soon as BioViva is successfull many more competitors will enter the field.

Posted by: Claus Elser at April 20th, 2016 3:52 AM

I hadn't known about Bioviva, so I'm glad I read this article. I am happy to see companies begin to avoid dealing with the FDA by moving overseas. It's a big world, and there are plenty of places where experimental treatments can be pursued without excessive regulation.

It seems to me that as we start to see more companies like Bioviva developing or offering experimental treatments, we are going to need independent companies to vet and rate these offshore clinics in a reputable way. There WILL be some medical disasters and fraud, and confidence could be improved through such private a rating system, as well as many lives save.

Posted by: Paul Rattner at April 20th, 2016 5:00 AM

@Claus: It's not my opinion what appears in the video. I even don't appear in it. What's in the video are testimonials (not opinions) of people that work in the stem cells field and that have seen many examples where "countless patients" didn't quite "benefited greatly from this sort of approach." It can't be dismissed as simply my opinion.

Posted by: Antonio at April 20th, 2016 8:03 AM

@Reason (and Jim): To be clear, however, the dystrophin mouse example is not a case that's relevant to the use of the CRISPR/Cas9 system to deliver new genetic material. The Duchenne muscular dystrophy (DMD) mice (and equivalent human patients) have a mutation in the dystrophin gene with a dysfunctional exon: to partially restore function, they were able to get away with "merely" sniping out the offending exon using a variant Cas9 that was easier to deliver with AAV. This allowed the cell to produce a truncated but still partially version of dystrophin, which then partially restored function. Their system didn't (and would not have been able to) deliver any new genetic material, let alone an entirely new gene, as would be required for (for instance) direct intraneuronal production of a novel lysosomal hydrolase for LysoSENS.

Posted by: Michael at April 20th, 2016 1:25 PM

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